Neurobehaviour between birth and 40 weeks’ gestation in infants born <30 weeks’ gestation and parental psychological wellbeing: predictors of brain development and child outcomes

BACKGROUND: Infants born <30 weeks’ gestation are at increased risk of long term neurodevelopmental problems compared with term born peers. The predictive value of neurobehavioural examinations at term equivalent age in very preterm infants has been reported for subsequent impairment. Yet there is little knowledge surrounding earlier neurobehavioural development in preterm infants prior to term equivalent age, and how it relates to perinatal factors, cerebral structure, and later developmental outcomes. In addition, maternal psychological wellbeing has been associated with child development. Given the high rate of psychological distress reported by parents of preterm children, it is vital we understand maternal and paternal wellbeing in the early weeks and months after preterm birth and how this influences the parent–child relationship and children’s outcomes. Therefore this study aims to examine how 1) early neurobehaviour and 2) parental mental health relate to developmental outcomes for infants born preterm compared with infants born at term. METHODS/DESIGN: This prospective cohort study will describe the neurobehaviour of 150 infants born at <30 weeks’ gestational age from birth to term equivalent age, and explore how early neurobehavioural deficits relate to brain growth or injury determined by magnetic resonance imaging, perinatal factors, parental mental health and later developmental outcomes measured using standardised assessment tools at term, one and two years’ corrected age. A control group of 150 healthy term-born infants will also be recruited for comparison of outcomes. To examine the effects of parental mental health on developmental outcomes, both parents of preterm and term-born infants will complete standardised questionnaires related to symptoms of anxiety, depression and post-traumatic stress at regular intervals from the first week of their child’s birth until their child’s second birthday. The parent–child relationship will be assessed at one and two years’ corrected age. DISCUSSION: Detailing the trajectory of infant neurobehaviour and parental psychological distress following very preterm birth is important not only to identify infants most at risk, further understand the parental experience and highlight potential times for intervention for the infant and/or parent, but also to gain insight into the effect this has on parent–child interaction and child development

A lifespan perspective on brain-behavioural heterogeneity following very preterm birth

Background: Very preterm birth (VPT; at ≤ 32 weeks’ gestation) occurs during a highly critical stage of brain development, which makes the VPT new-born brain highly vulnerable to insult and long-lasting neurodevelopmental sequelae. Structural and functional brain alterations may be at least partly responsible for the behavioural difficulties described in VPT individuals across the lifespan. However, there is marked heterogeneity in the extent and presence of behavioural difficulties amongst VPT individuals, making it challenging to identify those vulnerable to developing mental health problems and cognitive difficulties. Hence, identifying underlying neurobiological markers of specific behavioural outcomes could help recognize those VPT individuals who may benefit from targeted support.Objective: The overarching objective of this PhD thesis is to stratify the heterogeneity in behavioural outcomes exhibited by VPT individuals, explore structural and functional brain alterations which may characterise distinct behavioural subgroups, and investigate the influence of clinical and environmental factors. The thesis is organised into four experimental studies addressing the following specific aims:o Study #1: to identify differences in neonatal structural brain volumes in subgroups of VPT born children screening negatively and positively for autism spectrum conditions and to explore the role of developmental delay in mediating and moderating childhood autism traits.o Study #2: to parse heterogeneity in neonatal clinical and social risk and childhood behavioural outcomes using data-driven integrative consensus clustering and to explore differences in neonatal brain volumes and structural and functional connectivity between the resultant subgroups.o Study #3: to compare resting state functional connectivity and structural volumes between groups of children stratified both in terms of their clinical characteristics (i.e., VPT and fullterm (FT) birth) and their behavioural profiles identified using data-driven consensus clustering regardless of their gestational age at birth. Post-hoc analyses aimed to elucidate whether clinical and environmental factors differ within VPT or FT children belonging to distinct subgroups.o Study #4: to use the same approach employed in Study #3 to investigate resting state functional connectivity in a sample of adults born VPT and FT.Methodology: Distinct psychometric screening criteria (Study #1) and advanced data-driven clustering approaches (Studies #2-4) were used to parse behavioural heterogeneity at different time points throughout development: toddlerhood (Study #1), early childhood (Study #2), middle childhood (Study #3), and adulthood (Study #4). Magnetic resonance (MR) imaging data were collected and analysed using advanced whole-brain approaches such as Tensor Based Morphometry, Tract Based Spatial Statistics, graph theory metrics, and Network Based Statistic to quantify brain volumes and structural and functional connectivity patterns characterising behavioural heterogeneity.Study participants: Participants were drawn from two cohort studies: (i) the Evaluation of Preterm Imaging Study (ePrime), which evaluated brain development using multi-modal MR imaging (at term equivalent age and at 7-12 years) and behavioural assessments (at 2, 4-7, and 7-12 years); and (ii) the University College Hospital London (UCHL) study, which studied adults (median age 30 years) using multi-modal MR imaging and behavioural assessments.Results:o Study #1: Smaller neonatal brainstem volumes and high levels of developmental delay were seen in one of two subgroups of VPT toddlers screening positively for autism according to different psychometric criteria, relative to those screening negatively. Developmental delay in this positively screening subgroup was seen to be mediating and moderating the onset of autism traits in childhood. Smaller neonatal cerebellar volumes differentiated between the two distinct subgroups of VPT children screening positively for autism, despite exhibiting similar extent of autism traits in early childhood. Together, results suggest the presence of distinct aetiological trajectories associated with autism traits.o Study #2: In early childhood, three data-driven behavioural subgroups of VPT children were delineated: (i) a ‘Resilient’ subgroup with favourable behavioural outcomes and a more cognitively stimulating home environment, (ii) an ‘At-risk’ subgroup with behavioural difficulties and high neonatal clinical risk, and (iii) an ‘Intermediate’ subgroup with intermediate behavioural outcomes, low neonatal clinical risk and a less cognitively stimulating home environment. Relative to the ‘Intermediate’ subgroup, the ‘Resilient’ subgroup displayed larger neonatal fronto-limbic regional volumes and functional connectivity and the ‘At-risk’ subgroup showed widespread fronto-temporo-limbic white matter alterations. These findings highlight the value of studying neonatal patterns of functional and structural brain development as potential biomarkers of childhood outcomes, as well as the importance of a supportive home environment to foster child development following VPT birth.o Study #3: Results show evidence of widespread volumetric alterations and increased functional connectivity in VPT children relative to controls. In middle childhood, stratifying the sample into two data-driven behavioural subgroups, independently of birth status identified: (i) a ‘General Difficulties’ subgroup displaying widespread decreases in functional connectivity and greater behavioural difficulties relative to a (ii) ‘General Resilience’ subgroup. A three-subgroup solution was also explored, identifying: a (I) ‘Neurodevelopmental Difficulties’ subgroup with socio-emotional and higher-order cognitive difficulties and reduced rostro-lateral prefrontal, brainstem, occipital, and cerebellar volumes, and a (II) ‘Psychiatric Difficulties’ subgroup exhibiting psychiatric and executive function difficulties with reduced dorsolateral prefrontal and cerebellar volumes, relative to a (III) ‘Typical Development’ subgroup. All brain differences, apart from cerebellar and occipital volumetric alterations, significantly differentiated between distinct data-driven behavioural subgroups after adjusting for preterm birth, highlighting the presence of VPT-specific neural alterations as well as unique neural patterns underlying behavioural difficulties in the general population, independently of birth status. Furthermore, VPT (but not FT) children belonging to Neurodevelopmental Difficulties or Psychiatric Difficulties subgroups displayed greater social risk relative to those in the Typical Development subgroup.o Study #4: Complex widespread patterns of both increased and decreased functional connectivity were found in VPT compared to FT born adults in default mode, visual, and ventral attention networks. In adulthood, when VPT and FT born adults were stratified in terms of their behavioural profiles (irrespective of preterm birth), two data-driven subgroups were identified: (i) an ‘At-risk’ subgroup with more behavioural difficulties and reduced functional connectivity in frontal opercular and insular areas relative to a (ii) ‘Resilient’ subgroup with more favourable behavioural outcomes. These results indicate that functional connectivity between the default mode, ventral attention, and visual networks characterise clinically defined groups (VPT and FT) and are different from the connectivity patterns that characterise adults subdivided in terms of their behavioural profiles (irrespective of birth group), which are anchored in insular and frontal opercular regions. Moreover, social risk was found to be greater within adults born VPT belonging to At-risk relative to Resilient subgroups, while this relationship was not identified in those born FT.Conclusions: Collectively, these findings indicate a long-lasting presence of neurodevelopmental heterogeneity within VPT and FT samples which seems to persist throughout the lifespan. Specific structural and functional alterations differentiating between distinct behavioural profiles across both VPT and FT samples are also identified; whereby alterations localised to fronto-temporolimbic regions seem to be characteristic of behavioural difficulties in VPT and FT samples regardless of their birth status, while alterations to brain regions including visual and cerebellar areas may be characterising biomarkers of outcomes specifically in VPT samples. Implications of these findings suggest a potential benefit of using MRI to detect neurobiological markers of behavioural outcomes, which can in turn guide the implementation of personalised interventions for those at-risk of developing specific behavioural difficulties. Results presented here also highlight the importance of fostering an enriching environment to probe resilience against developing behavioural difficulties, particularly for those born VPT.<br/

Born too early and too small: higher order cognitive function and brain at risk at ages 8–16

Prematurity presents a risk for higher order cognitive functions. Some of these deficits manifest later in development, when these functions are expected to mature. However, the causes and consequences of prematurity are still unclear. We conducted a longitudinal study to first identify clinical predictors of ultrasound brain abnormalities in 196 children born very preterm (VP; gestational age 32 weeks) and with very low birth weight (VLBW; birth weight 1500 g). At ages 8–16, the subset of VP-VLBW children without neurological findings (124) were invited for a neuropsychological assessment and an MRI scan (41 accepted). Of these, 29 met a rigorous criterion for MRI quality and an age, and gender-matched control group (n = 14) was included in this study. The key findings in the VP-VLBW neonates were: (a) 37% of the VP-VLBW neonates had ultrasound brain abnormalities; (b) gestational age and birth weight collectively with hospital course (i.e., days in hospital, neonatal intensive care, mechanical ventilation and with oxygen therapy, surgeries, and retinopathy of prematurity) predicted ultrasound brain abnormalities. At ages 8–16, VP-VLBW children showed: a) lower intelligent quotient (IQ) and executive function; b) decreased gray and white matter (WM) integrity; (c) IQ correlated negatively with cortical thickness in higher order processing cortical areas. In conclusion, our data indicate that facets of executive function and IQ are the most affected in VP-VLBW children likely due to altered higher order cortical areas and underlying WMThis study was supported by the Spanish Government Institute Carlos III (FIS Pl11/02860), Spanish Ministry of Health to MM-L, and the University of Castilla-La Mancha mobility Grant VA1381500149

Brain Damage and Visuospatial Impairments: Exploring Early Structure-Function Associations in Children Born Very Preterm

Background: To provide insight into early neurosensory development in children born very preterm, we assessed the association between early structural brain damage and functional visuospatial attention and motion processing from one to two years corrected age. Methods: In 112 children born at <32 weeks gestational age, we assessed brain damage and growth with a standardized scoring system on magnetic resonance imaging (MRI; 1.5 Tesla) scans performed at 29 to 35 weeks gestational age. Of the children with an MRI scan, 82 participated in an eye tracking-based assessment of visuospatial attention and motion processing (Tobii T60XL) at one year corrected age and 59 at two years corrected age. Results: MRI scoring showed good intra- and inter-rater reproducibility. At one year, 10% children had delayed attentional reaction times and 23% had delayed motion reaction times. Moderate to severe brain damage significantly correlated with s

Functional thalamocortical connectivity at term equivalent age and outcome at 2 years in infants born preterm

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Development of brain structures following perinatal cerebral lesions suggests the involvement of the cerebellum in the working memory network

openCrossed cerebro-cerebellar diaschisis in very preterm born individuals, following perinatal cerebral lesions, reveals functional connectivity between some cerebral areas involved in working memory (WM) and yet undefined cerebellar regions: this may support the role of the latter in the WM network. The cerebellum has long been associated with motor control and coordination. In the last two decades, researchers have studied its involvement in a broad range of cognitive functions, such as visuospatial attention and WM. In this overview, I define the brain regions activated by the WM network and their development in term- and very preterm- infants compared, according to the most recent studies. These findings could contribute to support the involvement of the cerebellum in non-motor functions, specifically in WM.Crossed cerebro-cerebellar diaschisis in very preterm born individuals, following perinatal cerebral lesions, reveals functional connectivity between some cerebral areas involved in working memory (WM) and yet undefined cerebellar regions: this may support the role of the latter in the WM network. The cerebellum has long been associated with motor control and coordination. In the last two decades, researchers have studied its involvement in a broad range of cognitive functions, such as visuospatial attention and WM. In this overview, I define the brain regions activated by the WM network and their development in term- and very preterm- infants compared, according to the most recent studies. These findings could contribute to support the involvement of the cerebellum in non-motor functions, specifically in WM

Neonatal motor functional connectivity and motor outcomes at age two years in very preterm children with and without high-grade brain injury

Preterm-born children have high rates of motor impairments, but mechanisms for early identification remain limited. We hypothesized that neonatal motor system functional connectivity (FC) would relate to motor outcomes at age two years; currently, this relationship is not yet well-described in very preterm (VPT; born \u3c32 weeks\u27 gestation) infants with and without brain injury. We recruited 107 VPT infants - including 55 with brain injury (grade III-IV intraventricular hemorrhage, cystic periventricular leukomalacia, post-hemorrhagic hydrocephalus) - and collected FC data at/near term-equivalent age (35-45 weeks postmenstrual age). Correlation coefficients were used to calculate the FC between bilateral motor and visual cortices and thalami. At two years corrected-age, motor outcomes were assessed with the Bayley Scales of Infant and Toddler Development, 3rd edition. Multiple imputation was used to estimate missing data, and regression models related FC measures to motor outcomes. Within the brain-injured group only, interhemispheric motor cortex FC was positively related to gross motor outcomes. Thalamocortical and visual FC were not related to motor scores. This suggests neonatal alterations in motor system FC may provide prognostic information about impairments in children with brain injury

Univariate and multivariate pattern analysis of preterm subjects: a multimodal neuroimaging study

Background: Widespread lasting functional connectivity (FC) and brain volume changes in cortices and subcortices after premature birth have been researched in recent studies. However, the relationship remains unclear between spontaneously slow blood oxygen dependent level (BOLD) fluctuations and gray matter volume (GMV) changes in specific brain areas, such as temporal insular cortices, and whether classification methods based on MRI could be successfully applied to the identification of preterm individuals. In this thesis I hypothesized that in prematurely born adults 1. Ongoing neural excitability and brain activity, as estimated by regional functional connectivity of resting state functional MRI (rs-fMRI) is accompanied with altered low-frequency fluctuations and neonatal complications; 2. Altered regional functional connectivity is connected with superimposed cerebral structural reductions; and 3. multivariate neuroanatomical and functional brain patterns could be treated as features to identify preterm subjects from term subjects individually. Methods: To investigate these hypotheses, the principal results of structural alterations were measured with voxel-based morphometry (VBM), while rs-fMRI outcomes were estimated with amplitude of low-frequency fluctuations (ALFF) in analysis with ninety-four very preterm/very low birth weight (VP/VLBW) and ninety-two full-term (FT) born young adults. Results: The results of the thesis support the hypotheses by showing that, in univariate results, first in VP/VLBW grownups, ALFF was decreased in the left lateral temporal cortices no matter with global signal regression, and this reduction was closely associated with neonatal complications and cognitive variables. Second overlapped brain regions were found between reduced ALFF and reduced brain volumes in the left temporal cortices, and positively associated with each other, demonstrating a potential relationship between VBM and ALFF in this brain area. In multimodal multivariate pattern recognition analysis (MVPA), the gray matter volume (GMV) classifier displayed a higher accuracy (80.7%) contrast with the ALFF classifier (77.4%). The late fusion of GMV and ALFF did not outperform single GMV modality classification by reaching 80.4% accuracy. Moderator analysis from both rs-fMRI and structural MRI (sMRI) uncovered that the neuro-prematurity performance was predominantly determined by neonatal complications. Conclusions: In conclusion, these outcomes exhibit the long term effects of premature labour on lateral temporal cortices, which changed in both ongoing BOLD fluctuations and decreased cerebral structural volumes. This thesis further provided evidence that multivariate pattern analysis such as support vector machine (SVM) may identify imaging-based biomarkers and reliably detect signatures of preterm birth

Univariate and multivariate pattern analysis of preterm subjects: a multimodal neuroimaging study

Background: Widespread lasting functional connectivity (FC) and brain volume changes in cortices and subcortices after premature birth have been researched in recent studies. However, the relationship remains unclear between spontaneously slow blood oxygen dependent level (BOLD) fluctuations and gray matter volume (GMV) changes in specific brain areas, such as temporal insular cortices, and whether classification methods based on MRI could be successfully applied to the identification of preterm individuals. In this thesis I hypothesized that in prematurely born adults 1. Ongoing neural excitability and brain activity, as estimated by regional functional connectivity of resting state functional MRI (rs-fMRI) is accompanied with altered low-frequency fluctuations and neonatal complications; 2. Altered regional functional connectivity is connected with superimposed cerebral structural reductions; and 3. multivariate neuroanatomical and functional brain patterns could be treated as features to identify preterm subjects from term subjects individually. Methods: To investigate these hypotheses, the principal results of structural alterations were measured with voxel-based morphometry (VBM), while rs-fMRI outcomes were estimated with amplitude of low-frequency fluctuations (ALFF) in analysis with ninety-four very preterm/very low birth weight (VP/VLBW) and ninety-two full-term (FT) born young adults. Results: The results of the thesis support the hypotheses by showing that, in univariate results, first in VP/VLBW grownups, ALFF was decreased in the left lateral temporal cortices no matter with global signal regression, and this reduction was closely associated with neonatal complications and cognitive variables. Second overlapped brain regions were found between reduced ALFF and reduced brain volumes in the left temporal cortices, and positively associated with each other, demonstrating a potential relationship between VBM and ALFF in this brain area. In multimodal multivariate pattern recognition analysis (MVPA), the gray matter volume (GMV) classifier displayed a higher accuracy (80.7%) contrast with the ALFF classifier (77.4%). The late fusion of GMV and ALFF did not outperform single GMV modality classification by reaching 80.4% accuracy. Moderator analysis from both rs-fMRI and structural MRI (sMRI) uncovered that the neuro-prematurity performance was predominantly determined by neonatal complications. Conclusions: In conclusion, these outcomes exhibit the long term effects of premature labour on lateral temporal cortices, which changed in both ongoing BOLD fluctuations and decreased cerebral structural volumes. This thesis further provided evidence that multivariate pattern analysis such as support vector machine (SVM) may identify imaging-based biomarkers and reliably detect signatures of preterm birth