Cortical growth from infancy to adolescence in preterm and term-born children.

Early life experiences can exert a significant influence on cortical and cognitive development. Very preterm birth exposes infants to several adverse environmental factors during hospital admission, which affect cortical architecture. However, the subsequent consequence of very preterm birth on cortical growth from infancy to adolescence has never been defined; despite knowledge of critical periods during childhood for establishment of cortical networks. Our aims were to: chart typical longitudinal cortical development and sex differences in cortical development from birth to adolescence in healthy term-born children; estimate differences in cortical development between children born at term and very preterm; and estimate differences in cortical development between children with normal and impaired cognition in adolescence. This longitudinal cohort study included children born at term (≥37 weeks' gestation) and very preterm (<30 weeks' gestation) with MRI scans at ages 0, 7 and 13 years (n = 66 term-born participants comprising 34 with one scan, 18 with two scans and 14 with three scans; n = 201 very preterm participants comprising 56 with one scan, 88 with two scans and 57 with three scans). Cognitive assessments were performed at age 13 years. Cortical surface reconstruction and parcellation were performed with state-of-the-art, equivalent MRI analysis pipelines for all time points, resulting in longitudinal cortical volume, surface area and thickness measurements for 62 cortical regions. Developmental trajectories for each region were modelled in term-born children, contrasted between children born at term and very preterm, and contrasted between all children with normal and impaired cognition. In typically developing term-born children, we documented anticipated patterns of rapidly increasing cortical volume, area and thickness in early childhood, followed by more subtle changes in later childhood, with smaller cortical size in females than males. In contrast, children born very preterm exhibited increasingly reduced cortical volumes, relative to term-born children, particularly during ages 0-7 years in temporal cortical regions. This reduction in cortical volume in children born very preterm was largely driven by increasingly reduced cortical thickness rather than area. This resulted in amplified cortical volume and thickness reductions by age 13 years in individuals born very preterm. Alterations in cortical thickness development were found in children with impaired language and memory. This study shows that the neurobiological impact of very preterm birth on cortical growth is amplified from infancy to adolescence. These data further inform the long-lasting impact on cortical development from very preterm birth, providing broader insights into neurodevelopmental consequences of early life experiences.

Growth of prefrontal and limbic brain regions and anxiety disorders in children born very preterm.

BACKGROUND: Children born very preterm (VP) display altered growth in corticolimbic structures compared with full-term peers. Given the association between the cortiocolimbic system and anxiety, this study aimed to compare developmental trajectories of corticolimbic regions in VP children with and without anxiety diagnosis at 13 years. METHODS: MRI data from 124 VP children were used to calculate whole brain and corticolimbic region volumes at term-equivalent age (TEA), 7 and 13 years. The presence of an anxiety disorder was assessed at 13 years using a structured clinical interview. RESULTS: VP children who met criteria for an anxiety disorder at 13 years (n = 16) displayed altered trajectories for intracranial volume (ICV, p < 0.0001), total brain volume (TBV, p = 0.029), the right amygdala (p = 0.0009) and left hippocampus (p = 0.029) compared with VP children without anxiety (n = 108), with trends in the right hippocampus (p = 0.062) and left medial orbitofrontal cortex (p = 0.079). Altered trajectories predominantly reflected slower growth in early childhood (0-7 years) for ICV (ß = -0.461, p = 0.020), TBV (ß = -0.503, p = 0.021), left (ß = -0.518, p = 0.020) and right hippocampi (ß = -0.469, p = 0.020) and left medial orbitofrontal cortex (ß = -0.761, p = 0.020) and did not persist after adjusting for TBV and social risk. CONCLUSIONS: Region- and time-specific alterations in the development of the corticolimbic system in children born VP may help to explain an increase in anxiety disorders observed in this population.

Motor performance and attention outcomes in children born very preterm.

AIM: To examine the relationship between motor performance and attention in children born very preterm and at term, and investigate the presence of individual profiles of motor and attention performance. METHOD: Attention and motor performance at 7 and 13 years were assessed in 197 children born very preterm (52.5% male) and 69 children born at term (47.8% male) between 2001 and 2003. Linear regression models were fitted including an interaction term for birth group. Subgroups of children with similar attention and motor performance profiles were identified using latent profile analysis. RESULTS: Balance was positively associated with all attention outcomes at both ages (p < 0.006). There were specific birth group interactions for aiming and catching and manual dexterity with attention at 13 years, with positive associations observed only for children born very preterm (p < 0.001). At 7 years, three profiles were observed: average attention and motor functioning; average motor functioning and low attention functioning; and low attention and motor functioning. At 13 years, two profiles of average attention and motor functioning emerged, as well as one profile of below-average attention and motor functioning. Children born very preterm were overrepresented in the lower functioning profiles (born very preterm 56%; born at term 29%). INTERPRETATION: Motor functioning at age 7 years may be a useful marker of later attention skills, particularly for children born very preterm who are at greater risk of poorer long-term cognitive outcomes. WHAT THIS PAPER ADDS: Balance was positively associated with attention in children born very preterm and at term. Relationships between motor performance and attention at age 13 years differed between children born very preterm and at term. Heterogeneous motor functioning and attention outcomes were noted for children born very preterm and at term. Children born very preterm were more likely to have lower attention and motor functioning profiles than children born at term. There was greater movement in motor functioning and attention profiles between the ages of 7 and 13 years in children born very preterm.

Investigating brain structural maturation in children and adolescents born very preterm using the brain age framework.

Very preterm (VP) birth is associated with an increased risk for later neurodevelopmental and behavioural challenges. Although the neurobiological underpinnings of such challenges continue to be explored, previous studies have reported brain volume and morphology alterations in children and adolescents born VP compared with full-term (FT)-born controls. How these alterations relate to the trajectory of brain maturation, with potential implications for later brain ageing, remains unclear. In this longitudinal study, we investigate the relationship between VP birth and brain development during childhood and adolescence. We construct a normative 'brain age' model to predict age over childhood and adolescence based on measures of brain cortical and subcortical volumes and cortical morphology from structural MRI of a dataset of typically developing children aged 3-21 years (n = 768). Using this model, we examined deviations from normative brain development in a separate dataset of children and adolescents born VP (<30 weeks' gestation) at two timepoints (ages 7 and 13 years) compared with FT-born controls (120 VP and 29 FT children at age 7 years; 140 VP and 47 FT children at age 13 years). Brain age delta (brain-predicted age minus chronological age) was, on average, higher in the VP group at both timepoints compared with controls, however this difference had a small to medium effect size and was not statistically significant. Variance in brain age delta was higher in the VP group compared with controls; this difference was significant at the 13-year timepoint. Within the VP group, there was little evidence of associations between brain age delta and perinatal risk factors or cognitive and motor outcomes. Under the brain age framework, our results may suggest that children and adolescents born VP have similar brain structural developmental trajectories to term-born peers between 7 and 13 years of age.

Brain tissue microstructural and free-water composition 13 years after very preterm birth.

There have been many studies demonstrating children born very preterm exhibit brain white matter microstructural alterations, which have been related to neurodevelopmental difficulties. These prior studies have often been based on diffusion MRI modelling and analysis techniques, which commonly focussed on white matter microstructural properties in children born very preterm. However, there have been relatively fewer studies investigating the free-water content of the white matter, and also the microstructure and free-water content of the cortical grey matter, in children born very preterm. These biophysical properties of the brain change rapidly during fetal and neonatal brain development, and therefore such properties are likely also adversely affected by very preterm birth. In this study, we investigated the relationship of very preterm birth (<30 weeks' gestation) to both white matter and cortical grey matter microstructure and free-water content in childhood using advanced diffusion MRI analyses. A total of 130 very preterm participants and 45 full-term control participants underwent diffusion MRI at age 13 years. Diffusion tissue signal fractions derived by Single-Shell 3-Tissue Constrained Spherical Deconvolution were used to investigate brain tissue microstructural and free-water composition. The tissue microstructural and free-water composition metrics were analysed using a voxel-based analysis and cortical region-of-interest analysis approach. Very preterm 13-year-olds exhibited reduced white matter microstructural density and increased free-water content across widespread regions of the white matter compared with controls. Additionally, very preterm 13-year-olds exhibited reduced microstructural density and increased free-water content in specific temporal, frontal, occipital and cingulate cortical regions. These brain tissue composition alterations were strongly associated with cerebral white matter abnormalities identified in the neonatal period, and concurrent adverse cognitive and motor outcomes in very preterm children. The findings demonstrate brain microstructural and free-water alterations up to thirteen years from neonatal brain abnormalities in very preterm children that relate to adverse neurodevelopmental outcomes.

Development of regional brain gray matter volume across the first 13 years of life is associated with childhood math computation ability for children born very preterm and full term.

Very preterm birth (VP; <32 weeks' gestation) is associated with altered brain gray matter development and lower math ability. In typically developing children, the neural correlates of math ability may change dynamically with age, though evidence in VP children is limited. In a prospective longitudinal cohort of children born VP and full term (FT), we aimed to investigate associations between 1) concurrent regional brain volumes and math ability at 7 (n = 148 VP; n = 34 FT) and 13-years (n = 130 VP; n = 46 FT), and 2) regional volumetric growth across childhood (term-equivalent age (TEA) to 7-years; 7 to 13-years) and math ability from 7 to 13-years, and improvement in ability from 7 to 13 years. For both aims we investigated whether associations differed between birth groups. Cross-sectionally, frontal, temporal and subcortical regional volumes were positively associated with math ability for both birth groups. For FT children, greater growth of specific temporal regions was associated with higher math ability, and greater improvements. For VP children, similar associations were only observed for growth from TEA to 7-years with 13-year ability and improvements in ability. In conclusion, VP birth appears to alter associations of brain development across the first 13 years with childhood math ability.

Investigating the brain structural connectome following working memory training in children born extremely preterm or extremely low birth weight.

Children born extremely preterm (EP, <28 weeks' gestation) or extremely low birth weight (ELBW, <1,000 g) are a vulnerable population at high risk of working memory impairments. We aimed to examine changes in the brain structural connectivity networks thought to underlie working memory performance, after completion of a working memory training program (Cogmed) compared with a placebo program in EP/ELBW children. This was a double-blind, placebo-controlled randomized trial (the Improving Memory in a Preterm Randomised Intervention Trial). Children born EP/ELBW received either the Cogmed or placebo program at 7 years of age (n = 91). A subset of children had magnetic resonance imaging of the brain immediately pre- and 2 weeks post-training (Cogmed n = 28; placebo n = 27). T1 -weighted and diffusion-weighted images were used to perform graph theoretical analysis of structural connectivity networks. Changes from pre-training to post-training in structural connectivity metrics were generally similar between randomized groups. There was little evidence that changes in structural connectivity metrics were related to changes in working memory performance from pre- to post-training. Overall, our results provide little evidence that the Cogmed working memory training program has training-specific effects on structural connectivity networks in EP/ELBW children.

White matter tracts related to memory and emotion in very preterm children.

BACKGROUND: Very preterm (VP) children are at risk of memory and emotional impairments; however, the neural correlates remain incompletely defined. This study investigated the effect of VP birth on white matter tracts traditionally related to episodic memory and emotion. METHODS: The cingulum, fornix, uncinate fasciculus, medial forebrain bundle and anterior thalamic radiation were reconstructed using tractography in 144 VP children and 33 full-term controls at age 7 years. RESULTS: Compared with controls, VP children had higher axial, radial, and mean diffusivities and neurite orientation dispersion, and lower volume and neurite density in the fornix, along with higher neurite orientation dispersion in the medial forebrain bundle. Support vector classification models based on tract measures significantly classified VP children and controls. Higher fractional anisotropy and lower diffusivities in the cingulum, uncinate fasciculus, medial forebrain bundle and anterior thalamic radiation were associated with better episodic memory, independent of key perinatal risk factors. Support vector regression models using tract measures did not predict episodic memory and emotional outcomes. CONCLUSIONS: Altered tract structure is related to adverse episodic memory outcomes in VP children, but further research is required to determine the ability of tract structure to predict outcomes of individual children. IMPACT: We studied white matter fibre tracts thought to be involved in episodic memory and emotion in VP and full-term children using diffusion magnetic resonance imaging and machine learning. VP children have altered fornix and medial forebrain bundle structure compared with full-term children. Altered tract structure can be detected using machine learning, which accurately classified VP and full-term children using tract data. Altered cingulum, uncinate fasciculus, medial forebrain bundle and anterior thalamic radiation structure was associated with poorer episodic memory skills using linear regression. The ability of tract structure to predict episodic memory and emotional outcomes of individual children based on support vector regression was limited.

Individual Attention Patterns in Children Born Very Preterm and Full Term at 7 and 13 Years of Age.

OBJECTIVE: To identify attention profiles at 7 and 13 years, and transitions in attention profiles over time in children born very preterm (VP; <30 weeks' gestation) and full term (FT), and examine predictors of attention profiles and transitions. METHODS: Participants were 167 VP and 60 FT children, evaluated on profiles across five attention domains (selective, shifting and divided attention, processing speed, and behavioral attention) at 7 and 13 years using latent profile analyses. Transitions in profiles were assessed with contingency tables. For VP children, biological and social risk factors were tested as predictors with a multinomial logistic regression. RESULTS: At 7 and 13 years, three distinct profiles of attentional functioning were identified. VP children were 2-3 times more likely to show poorer attention profiles compared with FT children. Transition patterns between 7 and 13 years were stable average, stable low, improving, and declining attention. VP children were two times less likely to have a stable average attention pattern and three times more likely to have stable low or improving attention patterns compared with FT children. Groups did not differ in declining attention patterns. For VP children, brain abnormalities on neonatal MRI and greater social risk at 7 years predicted stable low or changing attention patterns over time. CONCLUSIONS: VP children show greater variability in attention profiles and transition patterns than FT children, with almost half of the VP children showing adverse attention patterns over time. Early brain pathology and social environment are markers for attentional functioning.

Long-term development of white matter fibre density and morphology up to 13 years after preterm birth: A fixel-based analysis.

BACKGROUND: It is well documented that infants born very preterm (VP) are at risk of brain injury and altered brain development in the neonatal period, however there is a lack of long-term, longitudinal studies on the effects of VP birth on white matter development over childhood. Most previous studies were based on voxel-averaged, non-fibre-specific diffusion magnetic resonance imaging (MRI) measures, such as fractional anisotropy. In contrast, the novel diffusion MRI analysis framework, fixel-based analysis (FBA), enables whole-brain analysis of microstructural and macrostructural properties of individual fibre populations at a sub-voxel level. We applied FBA to investigate the long-term implications of VP birth and associated perinatal risk factors on fibre development in childhood and adolescence. METHODS: Diffusion images were acquired for a cohort of VP (born <30 weeks' gestation) and full-term (FT, ≥37 weeks' gestation) children at two timepoints: mean (SD) 7.6 (0.2) years (n â€‹= â€‹138 VP and 32 FT children) and 13.3 (0.4) years (n â€‹= â€‹130 VP and 45 FT children). 103 VP and 21 FT children had images at both ages for longitudinal analysis. At every fixel (individual fibre population within an image voxel) across the white matter, we compared FBA metrics (fibre density (FD), cross-section (FC) and a combination of these properties (FDC)) between VP and FT groups cross-sectionally at each timepoint, and longitudinally between timepoints. We also examined associations between known perinatal risk factors and FBA metrics in the VP group. RESULTS: Compared with FT children, VP children had lower FD, FC and FDC throughout the white matter, particularly in the corpus callosum, tapetum, inferior fronto-occipital fasciculus, fornix and cingulum at ages 7 and 13 years, as well as the corticospinal tract and anterior limb of the internal capsule at age 13 years. VP children also had slower FDC development in the corpus callosum and corticospinal tract between ages 7 and 13 years compared with FT children. Within VP children, earlier gestational age at birth, lower birth weight z-score, and neonatal brain abnormalities were associated with lower FD, FC and FDC throughout the white matter at both ages. CONCLUSIONS: VP birth and concomitant perinatal risk factors are associated with fibre tract-specific alterations to axonal development in childhood and adolescence.

White matter extension of the Melbourne Children's Regional Infant Brain atlas: M-CRIB-WM.

Brain atlases providing standardised identification of neonatal brain regions are key in investigating neurological disorders of early childhood. Our previously developed Melbourne Children's Regional Infant Brain (M-CRIB) and M-CRIB 2.0 neonatal brain atlases provide standardised parcellation of 100 brain regions including cortical, subcortical, and cerebellar regions. The aim of this study was to extend M-CRIB atlas coverage to include 54 white matter (WM) regions. Participants were 10 healthy term-born neonates that were used to create the initial M-CRIB atlas. WM regions were manually segmented based on T2 images and co-registered diffusion tensor imaging-based, direction-encoded colour maps. Our labelled regions imitate the Johns Hopkins University neonatal atlas, with minor anatomical modifications. All segmentations were reviewed and approved by a paediatric radiologist and a neurosurgery research fellow for anatomical accuracy. The resulting neonatal WM atlas comprises 54 WM regions: 24 paired regions, and six unpaired regions comprising five corpus callosum subdivisions, and one pontine crossing tract. Detailed protocols for manual WM parcellations are provided, and the M-CRIB-WM atlas is presented together with the existing M-CRIB cortical, subcortical, and cerebellar parcellations in 10 individual neonatal MRI data sets. The novel M-CRIB-WM atlas, along with the M-CRIB cortical and subcortical atlases, provide neonatal whole brain MRI coverage in the first multi-subject manually parcellated neonatal atlas compatible with atlases commonly used at older time points. The M-CRIB-WM atlas is publicly available, providing a valuable tool that will help facilitate neuroimaging research into neonatal brain development in both healthy and diseased states.

Working memory training and brain structure and function in extremely preterm or extremely low birth weight children.

This study in children born extremely preterm (EP; <28 weeks' gestational age) or extremely low birth weight (ELBW; <1,000 g) investigated whether adaptive working memory training using Cogmed® is associated with structural and/or functional brain changes compared with a placebo program. Ninety-one EP/ELBW children were recruited at a mean (standard deviation) age of 7.8 (0.4) years. Children were randomly allocated to Cogmed or placebo (45-min sessions, 5 days a week over 5-7 weeks). A subset had usable magnetic resonance imaging (MRI) data pretraining and 2 weeks posttraining (structural, n = 48; diffusion, n = 43; task-based functional, n = 18). Statistical analyses examined whether cortical morphometry, white matter microstructure and blood oxygenation level-dependent (BOLD) signal during an n-back working memory task changed from pretraining to posttraining in the Cogmed and placebo groups separately. Interaction analyses between time point and group were then performed. There was a significant increase in neurite density in several white matter regions from pretraining to posttraining in both the Cogmed and placebo groups. BOLD signal in the posterior cingulate and precuneus cortices during the n-back task increased from pretraining to posttraining in the Cogmed but not placebo group. Evidence for group-by-time interactions for the MRI measures was weak, suggesting that brain changes generally did not differ between Cogmed and placebo groups. Overall, while some structural and functional MRI changes between the pretraining and posttraining period in EP/ELBW children were observed, there was little evidence of training-induced neuroplasticity, with changes generally identified in both groups. Trial registration Australian New Zealand Clinical Trials Registry, anzctr.org.au; ACTRN12612000124831.

Basal ganglia and thalamic tract connectivity in very preterm and full-term children; associations with 7-year neurodevelopment.

BACKGROUND: Altered basal ganglia and thalamic connectivity may be critical for cognitive, motor and behavioural impairments common to very preterm (<32 weeks' gestational age) children. This study aims to (1) compare corticostriatal and thalamocortical tract connectivity between very preterm and term-born children at 7 years of age; (2) explore tract connectivity associations with 7-year neurodevelopmental outcomes, and whether these relationships differed between groups. METHODS: Eighty-three very preterm and 19 term-born (≥37 weeks' gestational age) children underwent structural and diffusion magnetic resonance imaging and had a neuropsychological assessment at 7 years. Corticostriatal and thalamocortical tracts were reconstructed and white matter connectivity was estimated with apparent fibre density. RESULTS: Compared with term-born controls, very preterm children had decreased connectivity in tracts linking the caudate to right motor areas (-10%, p = 0.03) and the thalamus with left motor areas (-5.7%, p = 0.03). Reduced connectivity in corticostriatal and thalamocortical tracts was associated with adverse motor functioning in both groups (p = 0.06). Decreased connectivity of the left caudate and putamen with the lateral prefrontal cortex was associated with lower reading performance for controls (p = 0.06). CONCLUSION: Corticostriatal and thalamocortical tracts are vulnerable to very preterm birth. Poorer connectivity in these tracts may underlie the motor impairments observed in very preterm children.

Early life predictors of brain development at term-equivalent age in infants born across the gestational age spectrum.

BACKGROUND: It is well established that preterm infants have altered brain development compared with full-term (FT; ≥37 weeks' gestational age [GA]) infants, however the perinatal factors associated with brain development in preterm infants have not been fully elucidated. In particular, perinatal predictors of brain development may differ between very preterm infants (VP; <32 weeks' GA) and infants born moderate (MP; 32-33 weeks' GA) and late (LP; 34-36 weeks' GA) preterm, but this has not been studied. This study aimed to investigate the effects of early life predictors on brain volume and microstructure at term-equivalent age (TEA; 38-44 weeks), and whether these effects differ for GA groups (VP, MP, LP or FT). METHODS: Structural images from 328 infants (91 VP, 63 MP, 104 LP and 70 FT) were segmented into white matter, cortical grey matter, cerebrospinal fluid, subcortical grey matter, brainstem and cerebellum. Cortical grey matter and white matter images were analysed using voxel-based morphometry. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) images from 361 infants (92 VP, 69 MP, 120 LP and 80 FT) were analysed using Tract-Based Spatial Statistics. Relationships between early life predictors (birthweight standard deviation score [BWSDS], multiple birth, sex, postnatal growth and social risk) and global brain volumes were analysed using linear regressions. Relationships between early life predictors and regional brain volumes and diffusion measures were analysed using voxelwise non-parametric permutation testing. RESULTS: Male sex was associated with higher global volumes of all tissues and higher regional volumes throughout much of the cortical grey matter and white matter, particularly in the FT group. Male sex was also associated with lower FA and higher AD, RD and MD in the optic radiation, external and internal capsules and corona radiata, and these associations were generally similar between GA groups. Higher BWSDS was associated with higher global volumes of all tissues and higher regional volumes in much of the cortical grey matter and white matter in all GA groups, as well as higher FA and lower RD and MD in many major tracts (corpus callosum, optic radiation, internal and external capsules and corona radiata), particularly in the MP and LP groups. Multiple birth and social risk also showed associations with global and regional volumes and regional diffusion values which varied by GA group, but these associations were not independent of the other early life predictors. Postnatal growth was not associated with brain volumes or diffusion values. CONCLUSION: Early life predictors of brain volumes and microstructure at TEA include sex, BWSDS, multiple birth and social risk, which have different effects based on GA group at birth. This study improves knowledge of the perinatal factors associated with brain abnormalities in infants born across the prematurity spectrum.

Changes in neonatal regional brain volume associated with preterm birth and perinatal factors.

BACKGROUND: Preterm birth is associated with altered brain development, with younger gestational age (GA) at birth often associated with greater brain volume reduction. Such volume alterations at term equivalent age (TEA) have been found with differing magnitude across different brain regions, although this has mostly been investigated with regards to whole tissue volumes and large-scale subdivisions. In addition to degree of prematurity, many other perinatal factors have been found to influence brain structure and development in infants born preterm. We aimed to clarify the relationships between degree of prematurity and regional brain volumes at TEA, and between perinatal factors and regional brain volumes at TEA, in finer spatial detail. METHODS: 285 preterm and term-born infants (GA at birth 24.6-42.1 weeks; 145 female; 59 born at term) were scanned at TEA. Data on perinatal factors were obtained by chart review, including sex, multiple birth, birthweight standard deviation (SD) score, postnatal growth and social risk. The Melbourne Children's Regional Infant Brain (M-CRIB) atlas was registered to the current sample, then 100 brain regions were labelled for volumetric analyses. Linear regressions with generalised estimating equations and likelihood ratio tests were performed to investigate whether GA at birth or perinatal factors were associated with regional volumes at TEA. RESULTS: Younger GA at birth was associated with smaller volumes at TEA in some regions including bilateral cerebral white matter, middle temporal gyri, amygdalae, pallidum and brainstem. In other regions, younger GA at birth was associated with larger volumes, including in primary visual, motor and somatosensory cortices. Positive associations between perinatal factors and regional volumes at TEA were found in many brain regions for birthweight SD score, and male sex, independent of GA at birth. These associations were seen on both univariable analyses, and multivariable analyses controlling for other perinatal factors. Social risk and multiple birth were generally not associated with regional brain volumes, and postnatal growth was associated with volume in many regions only after adjusting for other perinatal factors. CONCLUSIONS: These results elucidate regional brain volume differences associated with preterm birth and perinatal factors at a more detailed parcellated level than previously reported, and contribute to understanding of the complex array of correlates of preterm birth.

Nutrition, Growth, Brain Volume, and Neurodevelopment in Very Preterm Children.

OBJECTIVE: To explore the associations between nutrition in the first 28 days after birth with somatic growth from birth to term-equivalent age, brain volumes at term-equivalent age, and neurodevelopment at 24 months of corrected age. STUDY DESIGN: Prospective cohort study of 149 infants born from 2011 to 2014 at <30 weeks of gestation in a tertiary neonatal nursery in Australia. The following data were collected: average daily energy, protein, fat, and carbohydrate intakes from birth until 28 days, and the difference in weight and head circumference z scores between birth and term-equivalent. Total brain tissue volumes were calculated from brain magnetic resonance imaging at term-equivalent age. Children were assessed at 2 years of corrected age with the Bayley Scales of Infant and Toddler Development-Third Edition. Relationships of nutritional variables with growth, brain volumes, and cognitive, language, and motor development were explored using linear regression. RESULTS: Complete nutritional data were available for 116 (78%) of the cohort. A 1 g/kg/day higher mean protein intake was associated with a mean increase in weight z score per week of 0.05 (95% CI 0.05, 0.10; P = .04). There was a lack of evidence for associations of any nutritional variables with head circumference growth, with brain volumes at term-equivalent age, or with 2-year neurodevelopment. CONCLUSIONS: Only higher protein intakes in the first 28 days after birth were associated with better weight growth between birth and term-equivalent age in very preterm infants. Nutrition in the first 28 days was otherwise not substantially related to brain size or to neurodevelopmental outcomes.

Thirteen-Year Outcomes in Very Preterm Children Associated with Diffuse Excessive High Signal Intensity on Neonatal Magnetic Resonance Imaging.

OBJECTIVE: To investigate the association between white matter diffuse excessive high signal intensity (DEHSI) on neonatal magnetic resonance imaging in very preterm infants and neurobehavioral outcomes at the age of 13 years. STUDY DESIGN: Magnetic resonance images of very preterm children (<30 weeks gestational age or <1250 g birth weight) were evaluated at term-equivalent age with DEHSI classified into 5 grades. Additionally, visibility of the posterior periventricular crossroads was assessed. General intelligence, memory, attention, executive function, motor abilities, and behavior were examined in 125 children at age 13 years and related to DEHSI grades using linear regression. RESULTS: DEHSI was detected in 93% of infants; 21% grade 1, 22% grade 2, 32% grade 3, and 18% grade 4. Neurobehavioral outcomes were similar for all DEHSI groups. There was weak evidence that higher DEHSI grades related to higher verbal IQ and attention and that lower DEHSI grades related to better planning ability. Adjustment for gestational age, birth weight standard score, and sex further weakened these effects. Only 12 children had invisible posterior crossroads and showed slightly poorer outcomes at 13 years of age. CONCLUSIONS: There was little evidence that neonatal DEHSI serves as a sensitive biomarker for later impairment. Further investigation on the importance of invisible posterior periventricular crossroads in larger samples is needed.

Brain structure and neurological and behavioural functioning in infants born preterm.

AIM: To examine: (1) relationships between brain structure, and concurrently assessed neurological and behavioural functioning, in infants born preterm at term-equivalent age (TEA; approximately 38-44wks); and (2) whether brain structure-function relationships differ between infants born very (24-29wks) and moderate-late (32-36wks) preterm. METHOD: A total of 257 infants (91 very preterm, 166 moderate-late preterm; 120 males, 137 females) had structural magnetic resonance imaging (MRI) and neurological and behavioural assessments (Prechtl's general movements assessment, Neonatal Intensive Care Unit Network Neurobehavioral Scale [NNNS] and Hammersmith Neonatal Neurological Examination [HNNE]). Two hundred and sixty-three infants (90 very preterm, 173 moderate-late preterm; 131 males, 132 females) had diffusion MRI and assessments. Associations were investigated between assessment scores and global brain volumes using linear regressions, regional brain volumes using Voxel-Based Morphometry, and white matter microstructure using Tract-Based Spatial Statistics. RESULTS: Suboptimal scores on some assessments were associated with lower fractional anisotropy and/or higher axial, radial, and mean diffusivities in some tracts: NNNS attention and reflexes, and HNNE total score and tone, were associated with the corpus callosum and optic radiation; NNNS quality of movement with the corona radiata; HNNE abnormal signs with several major tracts. Brain structure-function associations generally did not differ between the very and moderate-late preterm groups. INTERPRETATION: White matter microstructural alterations may be associated with suboptimal neurological and behavioural performance in some domains at TEA in infants born preterm. Brain structure-function relationships are similar for infants born very preterm and moderate-late preterm. WHAT THIS PAPER ADDS: Brain volume is not related to neurological/behavioural function in infants born preterm at term. White matter microstructure is related to some neurological/behavioural domains at term. Brain-behaviour relationships are generally similar for infants born very preterm and moderate-late preterm.

ESTRUCTURA CEREBRAL Y FUNCIONAMIENTO NEUROLÓGICO Y CONDUCTUAL EN LACTANTES PREMATUROS: OBJETIVO: Examinar: (1) las relaciones entre la estructura del cerebro y el funcionamiento neurológico y conductual evaluado simultáneamente en bebés nacidos prematuros a la edad equivalente al término (EET; aproximadamente 38 a 44 semanas); (2) si las relaciones estructura-función cerebral difieren entre los bebés nacidos muy prematuros (24-29 semanas) y prematuros-moderados-tardíos (32-36 semanas). MÉTODO: Un total de 257 bebés (91 muy prematuros, 166 prematuros moderados tardíos; 120 varones, 137 mujeres) tuvieron imágenes de resonancia magnética estructural (IRM) y evaluaciones neurológicas y conductuales (evaluación general de los movimientos de Prechtl, red de unidades de cuidados intensivos neonatales, escala neuroconductual [NNNS] y Hammersmith Neonatal Neurological Examination [HNNE]). Doscientos sesenta y tres bebés (90 muy prematuros, 173 moderados tardíos; 131 varones, 132 mujeres) se sometieron a RMN de difusión y evaluaciones. Se investigaron las asociaciones entre los puntajes de evaluación y los volúmenes cerebrales globales utilizando regresiones lineales, los volúmenes cerebrales regionales utilizando Morfometría Basada en Voxel y la microestructura de la materia blanca utilizando Estadísticas Espaciales Basadas en Tractos. RESULTADOS: Las puntuaciones subóptimas en algunas evaluaciones se asociaron con una menor anisotropía fraccional y / o mayores difusividades axiales, radiales y medias en algunos tractos: la atención y los reflejos NNNS, y la puntuación total y el tono HNNE, se asociaron con el cuerpo calloso y la radiación óptica; Calidad de movimiento NNNS con la corona radiata; Signos anormales de HNNE con varios tractos importantes. Las asociaciones estructura-función cerebral generalmente no difirieron entre los grupos prematuros muy moderados y tardíos. INTERPRETACIÓN: Las alteraciones microestructurales de la materia blanca pueden asociarse con un desempeño neurológico y de comportamiento subóptimo en algunos dominios neurológicos y conductuales en bebés nacidos prematuros evaluados a la EET. Las relaciones cerebro-estructura-comportamiento son similares para los bebés nacidos muy prematuros y para los prematuros moderados-tardíos.

ESTRUTURA CEREBRAL E FUNCIONAMENTO NEUROLÓGICO E COMPORTAMENTAL EM LACTENTES NASCIDOS PREMATUROS: OBJETIVO: Examinar: (1) relações entre estrutura cerebral, e funcionamento neurológico e comportamental avaliados simultaneamente, em lactentes nascidos prematuros na idade equivalente ao termo (IET; aproximadamente 38-44 semanas); 2) se a relação entre estrutura e função cerebral difere entre crianças nascidas muito prematuras (24-29sem) e moderadas-tardias (32-36sem). MÉTODO: Um total de 257 lactentes (91 muito prematuros, 166 prematuros moderados-tardios; 120 do sexo masculino, 137 do sexo feminino) tiveram imagens de ressonância magnética (IRM) e avaliações neurológicas e comportamentais (avaliação dos movimentos gerais de Prechtl, Escala Neurocomportamental da rede de Unidade de Cuidados Intensivos Neonatais [NNNS] e o Exame Neurológico Neonatal de Hammersmith [HNNE]). Duzentos e sessenta e três lactentes (90 muito prematuros, 173 prematuros moderados-tardios; 131 do sexo masculino, 132 do sexo feminino) relizaram IRM por difusão e as demais avaliações. Associações foram investigadas entre os escores das avaliações e volumes cerebrais globais usando regressões lineares, volumens cerebrais regionais usando Morfometria baseada em voxels, e micro-estrutura da substância branca usando Estatística especial baseada em tractos. RESULTADOS: Escores subótimos em algumas avaliações foram associada scom menor anisotropia fractional e/ou maior difusividade axial, radial e média em alguns tractos: atenção e reflexos no NNNS, escore total e de tônus no HNNE, foram associados com o corpo caloso e radiação óptica; qualidade do movimento no NNNS com a coroa radiada; sinais anormais no HNNE com vários tractos importantes. Associações entre estrutura e função do cérebro geralmente não diferiram entre os grupos de prematuros muito prematuros e moderados-tardios. INTERPRETAÇÃO: Alterações da microestrutura da substância branca podem estar associadas a desempenho neurológico e comportamental subótimos em alguns domínios na IET em lactentes prematuros. Relações entre estrutura e função cerebral são similares para lactentes muito prematuros e moderados-tardios.

Very preterm children at risk for developmental coordination disorder have brain alterations in motor areas.

AIM: Brain alterations in very preterm children at risk for developmental coordination disorder were investigated. METHODS: Infants born very preterm with gestation age <30 weeks or birthweight <1250 g were recruited from Royal Women's Hospital Melbourne from 2001 to 2003. Volumetric imaging was performed at term equivalent age; at seven years, volumetric imaging and diffusion tensor imaging were performed. At seven years, 53 of 162 children without cerebral palsy had scores ≤16th percentile on the Movement Assessment Battery for Children-Second Edition and were considered at risk for developmental coordination disorder. RESULTS: At term equivalent age, smaller brain volumes were found for total brain tissue, cortical grey matter, cerebellum, caudate accumbens, pallidum and thalamus in children at risk for developmental coordination disorder (p < 0.05); similar patterns were present at seven years. There was no evidence for catch-up brain growth in at-risk children. At seven years, at-risk children displayed altered microstructural organisation in many white matter tracts (p < 0.05). CONCLUSION: Infants born very preterm at risk for developmental coordination disorder displayed smaller brain volumes at term equivalent age and seven years, and altered white matter microstructure at seven years, particularly in motor areas. There was no catch-up growth from infancy to seven years.

Long-Term Academic Functioning Following Cogmed Working Memory Training for Children Born Extremely Preterm: A Randomized Controlled Trial.

OBJECTIVE: To assess the effectiveness of Cogmed Working Memory Training compared with a placebo program in improving academic functioning 24 months post-training in extremely preterm/extremely low birth weight 7-year-olds. STUDY DESIGN: A multicenter double-blind, placebo-controlled randomized controlled trial was conducted across all tertiary neonatal hospitals in the state of Victoria, Australia. Participants were 91 extremely preterm/extremely low birth weight 7-year-old children born in Victoria in 2005. Children were randomly assigned to either the Cogmed or placebo arm and completed the Cogmed or placebo program (20-25 sessions of 35-40 minutes duration) at home over 5-7 weeks. Academic achievement (word reading, spelling, sentence comprehension, and mathematics) was assessed 24 months post-training, as well as at 2 weeks and 12 months post-training, via standardized testing inclusive of working memory, attention, and executive behavior assessments. Data were analyzed using an intention-to-treat approach with mixed-effects modeling. RESULTS: There was little evidence of any benefits of Cogmed on academic functioning 24 months post-training, as well as on working memory, attention, or executive behavior at any age up to 24 months post-training compared with the placebo program. CONCLUSIONS: We currently do not recommend administration of Cogmed for early school-aged children born extremely preterm/extremely low birth weight to improve academic functioning. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12612000124831.