Infants born preterm are at high risk of long-term motor and neurocognitive deficits. In the majority of these infants structural MRI at the time of normal birth does not predict motor or cognitive ...outcomes accurately, and many infants without apparent brain lesions later develop motor and cognitive deficits. Thalamocortical connections are known to be necessary for normal brain function; they develop during late fetal life and are vulnerable to perinatal adversity. This study addressed the hypothesis that abnormalities in the functional connectivity between cortex and thalamus underlie neurocognitive impairments seen after preterm birth. Using resting state functional connectivity magnetic resonance imaging (fMRI) in a group of 102 very preterm infants without major focal brain lesions, we used partial correlations between thalamus and functionally-derived cortical areas to determine significant connectivity between cortical areas and thalamus, and correlated the parameter estimates of these connections with standardised neurocognitive assessments in each infant at 20 months of age. Pre-motor association cortex connectivity to thalamus correlates with motor function, while connectivity between primary sensory-motor cortex and thalamus correlates with cognitive scores. These results demonstrate the importance and vulnerability of functional thalamocortical connectivity development in the perinatal period for later neurocognitive functioning.
Background Abnormal macrostructural development of the cerebral cortex has been associated with hypoxia in infants with congenital heart disease ( CHD ). Animal studies have suggested that hypoxia ...results in cortical dysmaturation at the cellular level. New magnetic resonance imaging techniques offer the potential to investigate the relationship between cerebral oxygen delivery and cortical microstructural development in newborn infants with CHD . Methods and Results We measured cortical macrostructural and microstructural properties in 48 newborn infants with serious or critical CHD and 48 age-matched healthy controls. Cortical volume and gyrification index were calculated from high-resolution structural magnetic resonance imaging. Neurite density and orientation dispersion indices were modeled using high-angular-resolution diffusion magnetic resonance imaging. Cerebral oxygen delivery was estimated in infants with CHD using phase contrast magnetic resonance imaging and preductal pulse oximetry. We used gray matter-based spatial statistics to examine voxel-wise group differences in cortical microstructure. Microstructural development of the cortex was abnormal in 48 infants with CHD , with regions of increased fractional anisotropy and reduced orientation dispersion index compared with 48 healthy controls, correcting for gestational age at birth and scan (family-wise error corrected for multiple comparisons at P<0.05). Regions of reduced cortical orientation dispersion index in infants with CHD were related to impaired cerebral oxygen delivery ( R
=0.637; n=39). Cortical orientation dispersion index was associated with the gyrification index ( R
=0.589; P<0.001; n=48). Conclusions This study suggests that the primary component of cerebral cortex dysmaturation in CHD is impaired dendritic arborization, which may underlie abnormal macrostructural findings reported in this population, and that the degree of impairment is related to reduced cerebral oxygen delivery.
Very preterm (VPT; < 33 weeks’ gestation) toddlers screening positively for autism spectrum conditions (ASC) may display heterogenous neurodevelopmental trajectories. Here we studied neonatal brain ...volumes and childhood ASC traits evaluated with the Social Responsiveness Scale (SRS-2) in VPT-born toddlers (N = 371; median age 20.17 months) sub-divided into three groups based on their Modified-Checklist for Autism in Toddlers scores. These were: those screening positively failing at least 2 critical items (
critical-positive
); failing any 3 items, but less than 2 critical items (
non-critical-positive
); and screening negatively. Critical-positive scorers had smaller neonatal cerebellar volumes compared to non-critical-positive and negative scorers. However, both positive screening groups exhibited higher childhood ASC traits compared to the negative screening group, suggesting distinct aetiological trajectories associated with ASC outcomes.
This review integrates data on brain dysmaturation and acquired brain injury using fetal and neonatal magnetic resonance imaging (MRI), including the contribution of cardiovascular physiology to ...differences in brain development, and the relationship between brain abnormalities and subsequent neurological impairments in infants with congenital heart disease (CHD). The antenatal and neonatal period are critical for optimal brain development; the developing brain is particularly vulnerable to haemodynamic disturbances during this time. Altered cerebral perfusion and decreased cerebral oxygen delivery in the antenatal period can affect functional and structural brain development, while postnatal haemodynamic fluctuations may cause additional injury. In critical CHD, brain dysmaturation and acquired brain injury result from a combination of underlying cardiovascular pathology and surgery performed in the neonatal period. MRI findings in infants with CHD can be used to evaluate potential clinical risk factors for brain abnormalities, and aid prediction of functional outcomes at an early stage. In addition, information on timing of brain dysmaturation and acquired brain injury in CHD has the potential to be used when developing strategies to optimize neurodevelopment.
Resumen
Neuroimagen, fisiología cardiovascular y resultados funcionales en cardiopatías congénitas
Esta revisión integra datos sobre la inmadurez cerebral y lesiones cerebrales, utilizando resonancia magnética durante el período fetal y neonatal, en lactantes con cardiopatías congénitas. Se presenta la contribución de la fisiología cardiovascular en las alteraciones del desarrollo cerebral, y la relación entre anomalías cerebrales y subsecuentes alteraciones neurológicas.
El período prenatal y neonatal es crítico para el desarrollo óptimo del cerebro, el cerebro en desarrollo es particularmente vulnerable a las alteraciones hemodinámicas durante esta etapa. La alteración de la perfusión cerebral y la disminución del suministro de oxígeno cerebral en el período prenatal pueden afectar el desarrollo funcional y estructural del cerebro, mientras que las fluctuaciones hemodinámicas posnatales pueden causar lesiones adicionales.
En la cardiopatía congénita severa, la inmadurez cerebral y las lesiones cerebrales adquiridas son el resultado de una combinación de la patología cardiovascular subyacente y cirugías realizadas en el período neonatal. Los hallazgos de resonancia magnética en niños con cardiopatía congénita pueden utilizarse para evaluar posibles factores de riesgo clínicos de anomalías neurológicas, y pueden ayudar a predecir resultados funcionales en una etapa temprana. Además, información sobre la cronología del impacto en la madurez cerebral y las lesiones cerebrales adquiridas, en niños con cardiopatía congénita, tiene el potencial de ser utilizado en el desarrollo de estrategias para optimizar el desarrollo neurológico.
Resumo
Neuroimagem, fisiologia cardiovascular e evolução funcional nas cardiopatias congênitas
Esta revisão integra os dados sobre imaturidade cerebral e lesão cerebral adquirida, empregando as imagens de ressonância magnética fetal e neonatal (RNM) e incluindo a contribuição da fisiologia cardiovascular para as diferenças no desenvolvimento cerebral, e a relação entre as anormalidades cerebrais e as subsequentes lesões neurológicas nas crianças com cardiopatia congênita. Os períodos pré‐natal e neonatal são críticos para o ótimo desenvolvimento cerebral; o desenvolvimento cerebral é particularmente vulnerável aos distúrbios hemodinâmicos durante esses períodos. A alteração da perfusão cerebral e a diminuição da oferta de oxigênio para o cérebro no período pré‐natal podem afetar o desenvolvimento cerebral estrutural e funcional, enquanto que as flutuações hemodinâmicas no pós natal podem causar lesões adicionais. Na cardiopatia congênita grave, a imaturidade cerebral e a lesão cerebral adquirida são resultantes de uma combinação da patologia cardiovascular subjacente e da cirurgia realizada no período neonatal. Os achados da RNM nos lactentes com cardiopatia congênita podem ser empregados para se avaliar os fatores de risco clínico em potencial para anormalidades cerebrais e auxiliar no prognóstico da evolução funcional em um estágio precoce. Em contrapartida, a informação sobre o momento da imaturidade cerebral e da lesão cerebral adquirida na cardiopatia congênita tem o potencial para ser utilizado no estabelecimento de estratégias para otimizar o desenvolvimento neurológico.
What this paper adds
Infants with congenital heart disease show functional deficits in childhood and adolescence.
Neonatal brain dysmaturation and acquired brain injury can contribute to neurodevelopmental impairments.
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Premature birth is a major and growing problem. Investigations into neuroanatomical correlates and consequences of preterm birth are hampered by complex neonatal brain anatomy and unavailability of ...atlases and protocols covering the whole brain. We developed delineation protocols for the manual segmentation of cerebral magnetic resonance (MR) images from newborn infants into 50 regions with comprehensive coverage of the brain. We then segmented MR scans from 15 infants born preterm at median 29, range 26–35, weeks postmenstrual age and scanned at term-corrected age, and five term-born infants born at median 41, range 39–45, weeks postmenstrual age. Total and regional brain volumes were estimated in each infant, and regional volumes expressed as a fraction of total brain volume. Total brain volumes were higher with greater age at birth and at time of scan, but once corrected for age at scan there was no difference between preterm and term infants. Fractional age-corrected regional volumes were bigger unilaterally in terms in middle and inferior temporal gyri, anterior temporal lobe, fusiform gyrus and posterior cingulate gyrus. Fractional age-corrected regional volumes were larger in preterms bilaterally in hippocampus, amygdala, thalamus and lateral ventricles, left superior temporal gyrus and right caudate nucleus. These differences were not significant after correcting for multiple hypothesis testing, but suggest subtle differences between preterms and term-borns accessible to regional analysis. Detailed illustrated protocols are made available in the Appendix.
► New delineation protocols for manual segmentation of cerebral MRIs of newborns. ► 50 regions with comprehensive coverage of the brain. ► Segmented MR scans from 15 infants born preterm and five term-borns. ► Comparison of total, regional and fractional brain volumes in preterms and term-borns ► Investigation of alterations in brain development associated with preterm birth.
Compared to full-term (FT) born peers, children who were born very preterm (VPT; <32 weeks' gestation) are likely to display more cognitive and behavioral difficulties, including inattention, anxiety ...and socio-communication problems. In the published literature, such difficulties tend to be studied independently, thus failing to account for how different aspects of child development interact. The current study aimed to investigate children's cognitive and behavioral outcomes as interconnected, dynamically related facets of development that influence one another.
Participants were 93 VPT and 55 FT children (median age 8.79 years). IQ was evaluated with the Wechsler Intelligence Scale for Children-4
edition (WISC-IV), autism spectrum condition (ASC) traits with the social responsiveness scale-2
edition (SRS-2), behavioral and emotional problems with the strengths and difficulties questionnaire (SDQ), temperament with the temperament in middle childhood questionnaire (TMCQ) and executive function with the behavior rating inventory of executive functioning (BRIEF-2). Outcome measures were studied in VPT and FT children using Network Analysis, a method that graphically represents partial correlations between variables and yields information on each variable's propensity to form a
between other variables.
VPT and FT children exhibited marked topological differences.
(i.e., the variables most connected to others) in the VPT group network were: conduct problems and difficulties with organizing and ordering their environment. In the FT group network, the most important
were: difficulties with initiating a task or activity and prosocial behaviors, and greater emotional problems, such as lower mood.
These findings highlight the importance of targeting different aspects of development to support VPT and FT children in person-based interventions.
White matter tracts mature asymmetrically during development, and this development can be studied using diffusion magnetic resonance imaging. The aims of this study were i. to generate dynamic ...population-averaged white matter registration templates covering in detail the period from 25 weeks gestational age to term, and extending to 2 years of age based on DTI and fractional anisotropy, ii. to produce tract-specific probability maps of the corticospinal tracts, forceps major and forceps minor using probabilistic tractography, and iii. to assess the development of these tracts throughout this critical period of neurodevelopment. We found evidence for asymmetric development across the fiber bundles studied, with the corticospinal tracts showing earlier maturation (as measured by fractional anisotropy) but slower volumetric growth compared to the callosal fibers. We also found evidence for an anterior to posterior gradient in white matter microstructure development (as measured by mean diffusivity) in the callosal fibers, with the posterior forceps major developing at a faster rate than the anterior forceps minor in this age range. Finally, we report a protocol for delineating callosal and corticospinal fibers in extremely premature cohorts, and make available population-averaged registration templates and a probabilistic tract atlas which we hope will be useful for future neonatal and infant white-matter imaging studies.
Nonhypothesis-based MRI-analysis techniques including deformation-based morphometry and automated tissue segmentation have suggested that preterm infants at term-equivalent age have reduced tissue ...volume in the basal ganglia and thalami, which is most apparent among infants with supratentorial lesions. The aim of our study was to test this hypothesis by direct measurement of thalamic and lentiform nuclei volumes in preterm infants at term-equivalent age and term-born controls using manual volumetry.
Forty preterm infants at term-equivalent age (median gestational age: 29.5 weeks; median birth weight: 1.3 kg) and 8 term-born controls were examined using a 3-T Philips (Best, Netherlands) system. T1-weighted volume images and T2-weighted fast-spin echo pseudovolumes were acquired. There was no significant difference in postmenstrual age at image acquisition between the 2 groups. ImageJ 1.34 (National Institutes of Health, Bethesda, MD) was used for manual segmentations.
The median thalamic and lentiform nuclei volumes for preterm infants at term-equivalent age were 13.6 and 3.07 cm3, respectively, significantly smaller than term-control volumes of 16.3 and 5.6 cm3, respectively. Ten preterm infants at term-equivalent age had supratentorial lesions (intraventricular hemorrhage, periventricular leukomalacia, or hemorrhagic parenchymal infarction), and the median thalamic and lentiform volumes for this group were 10.4 and 1.7 cm3, respectively. When this group was excluded, the remaining infants who had mild or moderate diffuse excessive high signal intensity in the white matter on T2-weighted images had a smaller, yet significant, volume reduction compared with controls. Tissue volumes were not related to weight and gestational age at birth.
Manual volumetry confirms that preterm infants at term-equivalent age have reduced thalamic and lentiform volumes compared with controls. This was most marked among infants with supratentorial lesions but was also seen among those with nonfocal white matter abnormalities.
Abstract
Preterm-born children are at increased risk of lifelong neurodevelopmental difficulties. Group-wise analyses of magnetic resonance imaging show many differences between preterm- and ...term-born infants but do not reliably predict neurocognitive prognosis for individual infants. This might be due to the unrecognized heterogeneity of cerebral injury within the preterm group. This study aimed to determine whether atypical brain microstructural development following preterm birth is significantly variable between infants. Using Gaussian process regression, a technique that allows a single-individual inference, we characterized typical variation of brain microstructure using maps of fractional anisotropy and mean diffusivity in a sample of 270 term-born neonates. Then, we compared 82 preterm infants to these normative values to identify brain regions with atypical microstructure and relate observed deviations to degree of prematurity and neurocognition at 18 months. Preterm infants showed strikingly heterogeneous deviations from typical development, with little spatial overlap between infants. Greater and more extensive deviations, captured by a whole brain atypicality index, were associated with more extreme prematurity and predicted poorer cognitive and language abilities at 18 months. Brain microstructural development after preterm birth is highly variable between individual infants. This poorly understood heterogeneity likely relates to both the etiology and prognosis of brain injury.
Premature birth occurs during a period of rapid brain growth. In this context, interpreting clinical neuroimaging can be complicated by the typical changes in brain contrast, size and gyrification ...occurring in the background to any pathology. To model and describe this evolving background in brain shape and contrast, we used a Bayesian regression technique, Gaussian process regression, adapted to multiple correlated outputs. Using MRI, we simultaneously estimated brain tissue intensity on T1- and T2-weighted scans as well as local tissue shape in a large cohort of 408 neonates scanned cross-sectionally across the perinatal period. The resulting model provided a continuous estimate of brain shape and intensity, appropriate to age at scan, degree of prematurity and sex. Next, we investigated the clinical utility of this model to detect focal white matter injury. In individual neonates, we calculated deviations of a neonate's observed MRI from that predicted by the model to detect punctate white matter lesions with very good accuracy (area under the curve > 0.95). To investigate longitudinal consistency of the model, we calculated model deviations in 46 neonates who were scanned on a second occasion. These infants' voxelwise deviations from the model could be used to identify them from the other 408 images in 83% (T2-weighted) and 76% (T1-weighted) of cases, indicating an anatomical fingerprint. Our approach provides accurate estimates of non-linear changes in brain tissue intensity and shape with clear potential for radiological use.
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