Language performance and brain volumes, asymmetry, and cortical thickness in children born extremely preterm.

BACKGROUND: Children born preterm are more prone to have language difficulties. Few studies focus on children born extremely preterm (EPT) and the structural differences in language-related regions between these children and children born at term. METHODS: Our study used T1-weighted magnetic resonance imaging (MRI) scans to calculate the brain volumetry, brain asymmetry, and cortical thickness of language-related regions in 50 children born EPT and 37 term-born controls at 10 years of age. The language abilities of 41 of the children born EPT and 29 term-born controls were then assessed at 12 years of age, using the Wechsler Intelligence Scale for Children, Fifth Edition and the Clinical Evaluations of Language Fundamentals, Fourth Edition. The differences between MRI parameters and their associations with language outcomes were compared in the two groups. RESULTS: Brain volume and cortical thickness of language-related regions were reduced in children born EPT, but volumetric asymmetry was not different between children born EPT and at term. In children born EPT the brain volume was related to language outcomes, prior to adjustments for full-scale IQ. CONCLUSIONS: These findings expand our understanding of the structural correlates underlying impaired language performance in children born with EPT. IMPACT: The article expands understanding of the structure-function relationship between magnetic resonance imaging measurements of language-related regions and language outcomes for children born extremely preterm beyond infancy. Most literature to date has focused on very preterm children, but the focus in this paper is on extreme prematurity and language outcomes. While the brain volume and cortical thickness of language-related regions were reduced in children born EPT only the volume, prior to adjustment for full-scale IQ, was associated with language outcomes. We found no differences in volumetric asymmetry between children born EPT and at term.

Brain volumes and cortical thickness and associations with cognition in children born extremely preterm.

BACKGROUND: Children born extremely preterm (EPT) have altered brain volumes and cortical thickness and lower cognition than children born at term. Associations between these have remained largely unexplored, due to the lack of studies focusing on children born EPT. METHODS: Children underwent brain magnetic resonance imaging (MRI) at term and/or 10 years and cognitive assessments at 12 years. The study comprised of 42 children born EPT and 29 term-born controls with cognitive data and MRI data at 10 years, 25 children born EPT had MRI data at term age and 20 had longitudinal MRI data. RESULTS: Cognition was positively associated with brain volumes at 10 years, but negatively associated with cortical thickness at 10 years. Most associations between term age brain volumes and cognitive outcomes were non-significant for children born EPT. Growth from term to 10 years in children born EPT was not associated with cognition. Insular volume was positively associated with cognition in children born EPT. CONCLUSION: Imaging assessments at 10 years had similar associations to cognition in children born EPT and term-born controls. Insular volume could be a biomarker for cognitive outcome. Associations between brain volumetric growth and cognition require further investigation. IMPACT: This study investigated brain volumes, volumetric growth, and cortical thickness in children born extremely preterm, who have rarely been studied exclusively, and compared the data with term-born controls. In both groups, brain volumes at 10 years were positively associated with cognitive outcome at 12 years, but cortical thickness at 10 years was negatively associated with cognitive outcome at 12 years. Volumetric growth from term age to 10 years was not associated with cognitive outcome in the subset of children born extremely preterm with longitudinal data. Insular volume may be a potential biomarker for cognitive outcome in children born extremely preterm.

Brain structure in autoimmune Addison's disease.

Long-term disturbances in cortisol levels might affect brain structure in individuals with autoimmune Addison's disease (AAD). This study investigated gray and white matter brain structure in a cohort of young adults with AAD. T1- and diffusion-weighted images were acquired for 52 individuals with AAD and 70 healthy controls, aged 19-43 years, using magnetic resonance imaging. Groups were compared on cortical thickness, surface area, cortical gray matter volume, subcortical volume (FreeSurfer), and white matter microstructure (FSL tract-based spatial statistics). Individuals with AAD had 4.3% smaller total brain volume. Correcting for head size, we did not find any regional structural differences, apart from reduced volume of the right superior parietal cortex in males with AAD. Within the patient group, a higher glucocorticoid (GC) replacement dose was associated with smaller total brain volume and smaller volume of the left lingual gyrus, left rostral anterior cingulate cortex, and right supramarginal gyrus. With the exception of smaller total brain volume and potential sensitivity of the parietal cortex to GC disturbances in men, brain structure seems relatively unaffected in young adults with AAD. However, the association between GC replacement dose and reduced brain volume may be reason for concern and requires follow-up study.

Disrupted resting-sate brain network dynamics in children born extremely preterm.

The developing brain has to adapt to environmental and intrinsic insults after extremely preterm (EPT) birth. Ongoing maturational processes maximize their fit to the environment and this can provide a substrate for neurodevelopmental failures. Resting-state functional magnetic resonance imaging was used to scan 33 children born EPT, at < 27 weeks of gestational age, and 26 full-term controls at 10 years of age. We studied the capability of a brain area to propagate neural information (intrinsic ignition) and its variability across time (node-metastability). This framework was computed for the dorsal attention network (DAN), frontoparietal, default-mode network (DMN), and the salience, limbic, visual, and somatosensory networks. The EPT group showed reduced intrinsic ignition in the DMN and DAN, compared with the controls, and reduced node-metastability in the DMN, DAN, and salience networks. Intrinsic ignition and node-metastability values correlated with cognitive performance at 12 years of age in both groups, but only survived in the term group after adjustment. Preterm birth disturbed the signatures of functional brain organization at rest in 3 core high-order networks: DMN, salience, and DAN. Identifying vulnerable resting-state networks after EPT birth may lead to interventions that aim to rebalance brain function.

Discrete white matter abnormalities at age 8-11 years in children born extremely preterm are not associated with adverse cognitive or motor outcomes.

AIM: Little is known about the prevalence of discrete white matter abnormalities (WMA) beyond the first years in children born extremely preterm (EPT) and the relation to neurodevelopmental outcomes. Our aim was to investigate the prevalence of discrete WMA in children born EPT and the relationship to neonatal white matter injuries (WMI), white matter (WM) volume, WM diffusivity and neurodevelopment. METHODS: The study was a part of a longitudinal follow-up study of EPT neonates. All children were scanned at Karolinska University hospital 2004-2007 (neonates) and 2014-2015 (children at 8-11 years). WMA was qualitatively assessed by visual inspection. Developmental assessment was conducted at 12 years. RESULTS: In total, 112 children (median age 10.3 years, 56 girls) underwent MRI of the brain (68 EPT, 45 controls). In the EPT group, a subset had MRI around term equivalent age (n = 61). In the EPT group, the prevalence of discrete WMA at 8-11 years was 52%. There was a positive association between WMI at TEA and 8-11 years. There was no association between WMI and WM volumes or diffusivity at 8-11 years. Discrete WMA was not related to neurodevelopmental outcomes. CONCLUSION: Discrete WMA was prevalent in children born EPT at 8-11 years but were not related to neurodevelopmental outcomes.

Altered Gray Matter Structure and White Matter Microstructure in Patients with Congenital Adrenal Hyperplasia: Relevance for Working Memory Performance.

Congenital adrenal hyperplasia (CAH) has been associated with brain structure alterations, but systematic studies are lacking. We explore brain morphology in 37 (21 female) CAH patients and 43 (26 female) healthy controls, aged 16-33 years, using structural magnetic resonance imaging to estimate cortical thickness, surface area, volume, subcortical volumes, and white matter (WM) microstructure. We also report data on a small cohort of patients (n = 8) with CAH, who received prenatal dexamethasone (DEX). Patients with CAH had reduced whole brain volume (4.23%) and altered structure of the prefrontal, parietal, and superior occipital cortex. Patients had reduced mean FA, and reduced RD and MD, but not after correcting for brain volume. The observed regions are hubs of the visuospatial working memory and default mode (DMN) networks. Thickness of the left superior parietal and middle frontal gyri was associated with visuospatial working memory performance, and patients with CAH performed worse on this task. Prenatal treatment with DEX affected brain structures in the parietal and occipital cortex, but studies in larger cohorts are needed. In conclusion, our study suggests that CAH is associated with brain structure alterations, especially in the working memory network, which might underlie the cognitive outcome observed in patients.

Breakdown of Whole-brain Dynamics in Preterm-born Children.

The brain operates at a critical point that is balanced between order and disorder. Even during rest, unstable periods of random behavior are interspersed with stable periods of balanced activity patterns that support optimal information processing. Being born preterm may cause deviations from this normal pattern of development. We compared 33 extremely preterm (EPT) children born at < 27 weeks of gestation and 28 full-term controls. Two approaches were adopted in both groups, when they were 10 years of age, using structural and functional brain magnetic resonance imaging data. The first was using a novel intrinsic ignition analysis to study the ability of the areas of the brain to propagate neural activity. The second was a whole-brain Hopf model, to define the level of stability, desynchronization, or criticality of the brain. EPT-born children exhibited fewer intrinsic ignition events than controls; nodes were related to less sophisticated aspects of cognitive control, and there was a different hierarchy pattern in the propagation of information and suboptimal synchronicity and criticality. The largest differences were found in brain nodes belonging to the rich-club architecture. These results provide important insights into the neural substrates underlying brain reorganization and neurodevelopmental impairments related to prematurity.

Beyond the Epileptic Focus: Functional Epileptic Networks in Focal Epilepsy.

Focal epilepsy can be conceptualized as a network disorder, and the functional epileptic network can be described as a complex system of multiple brain areas that interact dynamically to generate epileptic activity. However, we still do not fully understand the functional architecture of epileptic networks. We studied a cohort of 21 patients with extratemporal focal epilepsy. We used independent component analysis of functional magnetic resonance imaging (fMRI) data. In order to identify the epilepsy-related components, we examined the general linear model-derived electroencephalography-fMRI (EEG-fMRI) time courses associated with interictal epileptic activity as intrinsic hemodynamic epileptic biomarkers. Independent component analysis revealed components related to the epileptic time courses in all 21 patients. Each epilepsy-related component described a network of spatially distributed brain areas that corresponded to the specific epileptic network in each patient. We also provided evidence for the interaction between the epileptic activity generated at the epileptic network and the physiological resting state networks. Our findings suggest that independent component analysis, guided by EEG-fMRI epileptic time courses, have the potential to define the functional architecture of the epileptic network in a noninvasive way. These data could be useful in planning invasive EEG electrode placement, guiding surgical resections, and more effective therapeutic interventions.

Making of the mind.

The essence of the mind is consciousness. It emerged early during evolution and ontogeny appears to follow the same process as phylogeny. Consciousness comes from multiple sources, including visual, auditory, sensorimotor and proprioceptive senses. These gradually combine during development to build a unified consciousness, due to the constant interactions between the brain, body, and environment. In the human the emergence of consciousness depends on the activation of the cortex by thalamocortical connections around 24 weeks after conception. Then, the human foetus can be potentially conscious, as it is aware of its body and reacts to touch, smell and sound and shows social expressions in response to external stimuli. However, it is mainly asleep and probably not aware of itself and its environment. In contrast, the newborn infant is awake after its first breaths of air and can be aware of its own self and others, express emotions and share feelings. The development of consciousness is a progressive, stepwise, structural and functional evolution of multiple intricate components. The infant fulfils some of the more basic criteria for consciousness. However, there are some important missing pieces at this stage, as it cannot remember the past and anticipate the future.

Poor Brain Growth in Extremely Preterm Neonates Long Before the Onset of Autism Spectrum Disorder Symptoms.

Preterm infants face an increased risk of autism spectrum disorder (ASD). The relationship between autism during childhood and early brain development remains unexplored. We studied 84 preterm children born at <27 weeks of gestation, who underwent neonatal magnetic resonance imaging (MRI) at term and were screened for ASD at 6.5 years. Full-scale intelligence quotient was measured and neonatal morbidities were recorded. Structural brain morphometric studies were performed in 33 infants with high-quality MRI and no evidence of focal brain lesions. Twenty-three (27.4%) of the children tested ASD positive and 61 (72.6%) tested ASD negative. The ASD-positive group had a significantly higher frequency of neonatal complications than the ASD-negative group. In the subgroup of 33 children, the ASD infants had reduced volumes in the temporal, occipital, insular, and limbic regions and in the brain areas involved in social/behavior and salience integration. This study shows that the neonatal MRI scans of extremely preterm children, subsequently diagnosed with ASD at 6.5 years, showed brain structural alterations, localized in the regions that play a key role in the core features of autism. Early detection of these structural alterations may allow the early identification and intervention of children at risk of ASD.

Intrinsic Functional Connectivity in Preterm Infants with Fetal Growth Restriction Evaluated at 12 Months Corrected Age.

Fetal growth restriction (FGR) affects brain development in preterm infants, but little is known about its effects on resting-state functional connectivity. We compared 20 preterm infants, born at <34 weeks of gestation with abnormal antenatal Doppler measurements and birth weights <10th percentile, with 20 appropriate for gestational age preterm infants of similar gestational age and 20 term infants. They were scanned without sedation at 12 months of age and screened for autistic traits at 26 months. Resting functional connectivity was assessed using group independent component analysis and seed-based correlation analysis. The groups showed 10 common resting-state networks involving cortical, subcortical regions, and the cerebellum. Only infants with FGR showed patterns of increased connectivity in the visual network and decreased connectivity in the auditory/language and dorsal attention networks. No significant differences between groups were found using seed-based correlation analysis. FGR infants displayed a higher frequency of early autism features, related to decreased connectivity involving the salience network, than term infants. These data suggest that FGR is an independent risk factor for disrupted intrinsic functional connectivity in preterm infants when they are 1-year old and provide more clues about the neurodevelopmental abnormalities reported in this population.

National population-based cohort study found that visual-motor integration was commonly affected in extremely preterm born children at six-and-a-half years.

AIM: This study aimed to explain the relationship between visual-motor integration (VMI) abilities and extremely preterm (EPT) birth, by exploring the influence of perinatal variables, cognition, manual dexterity and ophthalmological outcomes. METHODS: This was part of the population-based national Extremely Preterm Infant Study in Sweden (EXPRESS) study. We studied 355 children, born at a gestational age of <27 weeks from April 2004 to March 2007, and 364 term-born controls. At six-and-a-half years of age, we assessed VMI, cognitive function, motor skills and vision. VMI impairment was classified as <-1 standard deviation (SD). RESULTS: The mean (SD) VMI score was 87 (±12) in preterm children compared to 98 (±11) in controls (p < 0.001). VMI impairment was present in 55% of preterm infants and in 78% of children born at 22-23 weeks. Male sex and postnatal steroids showed a weak association with poorer visual-motor performance, whereas low manual dexterity and cognitive function showed a stronger association. CONCLUSION: Poor VMI performance was common in this EXPRESS cohort of children born EPT. Its strong association to cognition and manual dexterity confirms that all of these factors need to be taken into account when evaluating risks in preterm born children.

A Program Aimed at Reducing Anxiety in Pregnant Women Diagnosed With a Small-for-Gestational-Age Fetus: Evaluative Findings From a Spanish Study.

The objective of this study was to evaluate the effect of anxiety-reducing techniques including music therapy, sophrology, and creative visualization in pregnant women with a fetus diagnosed as small for gestational age and improved fetal and neonatal weight. This was a quasi-experimental study with a nonrandomized clinical trial design. We compared 2 groups of pregnant women with a fetus diagnosed as small for gestational age with no abnormalities on Doppler studies. The control group (n = 93) received standard care, and the intervention group (n = 65), in addition to standard care, underwent a program of 6 sessions led by a midwife or nurse who taught anxiety-reduction techniques. The State-Trait Anxiety Inventory (STAI) including trait and state subscales were completed by both groups at the start of the study, and only the STAI-State subscale was completed again at the end of the study. Comparisons between the 2 groups regarding fetal weight and centile and maternal STAI scores were performed using the t test and the χ test. There were no significant differences in the STAI-Trait scores between the 2 groups. There were statistically significant differences in the intervention group's STAI-State score percentiles between the start and the end of the study, being lower at the end of the study (P < .001). There were significant differences between the 2 groups in fetal weight trajectory on the basis of fetal weight: the intervention group had a larger weight gain (P < .005). The program designed to reduce anxiety in pregnant women was effective at reducing anxiety in the women in the intervention group, leading to a favorable fetal weight trajectory in this group.

Extremely Preterm-Born Infants Demonstrate Different Facial Recognition Processes at 6-10 Months of Corrected Age.

OBJECTIVES: To compare cortical hemodynamic responses to known and unknown facial stimuli between infants born extremely preterm and term-born infants, and to correlate the responses of the extremely preterm-born infants to regional cortical volumes at term-equivalent age. STUDY DESIGN: We compared 27 infants born extremely preterm (<28 gestational weeks) with 26 term-born infants. Corrected age and chronological age at testing were between 6 and 10 months, respectively. Both groups were exposed to a gray background, their mother's face, and an unknown face. Cerebral regional concentrations of oxygenated and deoxygenated hemoglobin were measured with near-infrared spectroscopy. In the preterm group, we also performed structural brain magnetic resonance imaging and correlated regional cortical volumes to hemodynamic responses. RESULTS: The preterm-born infants demonstrated different cortical face recognition processes than the term-born infants. They had a significantly smaller hemodynamic response in the right frontotemporal areas while watching their mother's face (0.13 µmol/L vs 0.63 µmol/L; P < .001). We also found a negative correlation between the magnitude of the oxygenated hemoglobin increase in the right frontotemporal cortex and regional gray matter volume in the left fusiform gyrus and amygdala (voxels, 25; r = 0.86; P < .005). CONCLUSION: At 6-10 months corrected age, the preterm-born infants demonstrated a different pattern in the maturation of their cortical face recognition process compared with term-born infants.

Brain Growth Gains and Losses in Extremely Preterm Infants at Term.

Premature exposure to the extrauterine environment negatively affects the brains' developmental trajectory. Our aim was to determine whether extremely preterm (EPT) infants, with no evidence of focal brain lesions, show morphological brain differences when compared with term-born infants. Additionally, we investigated associations between perinatal factors and neuroanatomical alterations. Conventional magnetic resonance imaging was acquired at term-equivalent age (TEA) from 47 EPT infants born before 27 weeks of gestation, and 15 healthy, term-born controls. Automatic segmentation and voxel-based morphometry-Diffeomorphic Anatomical Registration through Exponentiated Lie algebra (DARTEL) were used. Compared with controls, EPT infants displayed global reductions in cortical and subcortical gray matter, brainstem, and an increased cerebrospinal fluid volume. Regionally, they showed decreased volumes of all brain tissues, in particular cortical gray matter. Increased volumes of cortical gray and white matter were observed in regions involved in visual processing. Increasing prematurity, intraventricular hemorrhage grade I-II, and patent ductus arteriosus ligation were associated with decreased volumes and had a particular effect on the cerebellum. Concluding, EPT infants without focal brain lesions had an altered brain growth at TEA that particularly affected the gray matter, and varied when it came to the presence of perinatal risk factors. Brain growth gains in EPT infants may be related to a longer extrauterine experience.

Sex differences in outcome and associations with neonatal brain morphology in extremely preterm children.

OBJECTIVE: To investigate sex differences in neurologic and developmental outcomes in extremely preterm (EPT) children and explore associations with neonatal brain morphology. STUDY DESIGN: A population-based cohort of infants born at <27 weeks gestation underwent magnetic resonance imaging (MRI) at term equivalent age (n = 107). Voxel-based morphometry (n = 27) and tract-based spatial statistics (n = 29) were performed in infants with normal MRI findings. Neurologic and developmental assessment (using the Bayley Scales of Infant and Toddler Development-Third Edition [BSITD-III]) was performed at 30 months corrected age (n = 91). RESULTS: EPT boys had lower mean cognitive composite scores (P = .03) and lower mean language composite scores (P = .04) compared with EPT girls. Rates of cerebral palsy were similar in the 2 sexes. No perinatal factor explained the variance in outcomes. Visual inspection of T1- and T2-weighted MRI images found that delayed myelination was found more frequently in boys, whereas cerebellar abnormalities were more common in girls. In the subgroup of children with normal MRI findings (n = 27), boys had poorer cognitive function (P = .015) and language function (P = .008), despite larger volumes of cerebellar tissue (P = .029). In boys, cerebellar volume was positively correlated with BSITD-III cognitive and motor scores (P = .04 for both). In girls, white matter volume (P = .02) and cortical gray matter volume (P = .03) were positively correlated with BSITD-III language score. At the regional level, significant correlations with outcomes were found only in girls. CONCLUSION: Cognitive and language outcomes at age 30 months were poorer in boys. Sex-related differences were observed on neonatal structural MRI, including differences in the patterns of correlations between brain volumes and developmental scores at both global and regional levels.

Increased Resting-State Functional Connectivity in Patients With Autoimmune Addison Disease.

CONTEXT: Individuals with autoimmune Addison disease (AAD) take replacement medication for the lack of adrenal-derived glucocorticoid (GC) and mineralocorticoid hormones from diagnosis. The brain is highly sensitive to these hormones, but the consequence of having AAD for brain health has not been widely addressed. OBJECTIVE: The present study compared resting-state functional connectivity (rs-fc) of the brain between individuals with AAD and healthy controls. METHODS: Fifty-seven patients with AAD (33 female) and 69 healthy controls (39 female), aged 19 to 43 years were scanned with 3-T magnetic resonance imaging (MRI). RESULTS: Independent component and subsequent dual regression analyses revealed that individuals with AAD had stronger rs-fc compared to controls in 3 networks: the bilateral orbitofrontal cortex (OFC), the left medial visual and left posterior default mode network. A higher GC replacement dose was associated with stronger rs-fc in a small part of the left OFC in patients. We did not find any clear associations between rs-fc and executive functions or mental fatigue. CONCLUSION: Our results suggest that having AAD affects the baseline functional organization of the brain and that current treatment strategies of AAD may be one risk factor.

Identifying the cortical substrates of interictal epileptiform activity in patients with extratemporal epilepsy: An EEG-fMRI sequential analysis and FDG-PET study.

PURPOSE: The aim of this study was to apply sequential analysis of electroencephalography-functional magnetic resonance imaging (EEG-fMRI) data to study the cortical substrates related to the generation of the interictal epileptiform activity (IEA) in patients with pharmacoresistant extratemporal epilepsy. METHODS: We analyzed fMRI data from 21 children, adolescents, and young adults patients who showed frequent bursts or runs of spikes on EEG, by using the sequential analysis method. We contrasted consecutive fixed-width blocks of 10 s to obtain the relative variations in cerebral activity along the entire fMRI runs. Significant responses (p < 0.05, family-wise error (FWE) corrected), time-related to the IEA recorded on scalp EEG, were considered potential IEA cortical sources. These results were compared with those from the fluorodeoxyglucose-positron emission tomography (FDG-PET), intracranial EEG (two patients), and surgery outcome (eight patients). KEY FINDINGS: The typical IEA was recorded in all patients. After the sequential analysis, at least one significant blood oxygen level-dependent (BOLD) response spatially consistent with the presumed epileptogenic zone was found. These IEA-related activation areas coincided when superimposed with the hypometabolism depicted by the FDG-PET. These data were also consistent with the invasive EEG findings. Epileptic seizures were recorded in eight patients. A subset of IEA-associated fMRI activations was consistent the activations at seizure-onset determined by sequential analysis. The inclusion of the IEA-related areas in the resection rendered the patients seizure-free (five of eight operated patients). SIGNIFICANCE: The EEG-fMRI data sequential analysis could noninvasively identify cortical areas involved in the IEA generation. The spatial relationship of these areas with the cortical metabolic abnormalities depicted by the FDG-PET and their intrinsic relationship regarding the ictal-onset zone could be useful in epilepsy surgery planning.

Brain activity during visuospatial working memory in congenital adrenal hyperplasia.

CONTEXT: Patients with congenital adrenal hyperplasia (CAH) require life-long replacement of cortisol. Problems with cognitive function, especially working memory, have previously been identified, but the long-term effects of this disease on brain function are unknown. OBJECTIVE: We investigate brain activity during working memory in CAH compared to controls. DESIGN, SETTING, AND PARTICIPANTS: Twenty-nine individuals with CAH (17 females) and 40 healthy controls (24 females), 16-33 years, from a single research institute, underwent functional magnetic resonance imaging while doing a verbal and visuospatial working memory task. RESULTS: Individuals with CAH responded faster on the verbal task. Although we found no differences in BOLD response over the whole group, there were significant interactions with sex: CAH males had increased activity in the bilateral lateral superior occipital cortex, left supramarginal and angular gyri, left precuneus, left posterior cingulate cortex and bilateral cerebellum during decoding of the visuospatial task, while females showed decreased activity in these regions. CONCLUSIONS: Long-term cortisol imbalances do not seem to have a major impact on the functional brain responses during working memory in CAH. However, activity of the left dorsal visual stream in particular might be affected depending on sex. As the task employed may have been relatively easy, larger studies using more complex tasks are needed to further investigate this.

Extreme prematurity and perinatal risk factors related to extremely preterm birth are associated with complex patterns of regional brain volume alterations at 10 years of age: a voxel-based morphometry study.

Objective: Structural brain volumetric differences have been investigated previously in very preterm children. However, children born extremely preterm, at the border of viability, have been studied to a lesser degree. Our group previously analyzed children born extremely preterm at term using voxel-based morphometry. In this study, we aimed to examine regional gray and white matter differences for children born extremely preterm derived from the same cohort during childhood. We also aimed to explore the effect of perinatal risk factors on brain volumes in the same group. Methods: At 10 years of age, 51 children born extremely preterm (before 27 weeks and 0 days) and 38 term-born controls with high-quality 3.0 Tesla magnetic resonance images were included. Statistical analyses using voxel-based morphometry were conducted on images that were normalized using age-specific templates, modulated, and smoothed. Analyses were also performed in stratified groups of children born extremely preterm in the absence or presence of perinatal risk factors that have previously been shown to be associated with volumetric differences at term. Results: We found volumetric decreases in gray and white matter in the temporal lobes, gray matter decreases in the precuneus gyri, and white matter decreases in the anterior cingulum for children born extremely preterm (all p < 0.001, and pfwe < 0.05). Gray and white matter increases were predominantly observed in the right posterior cingulum and occipital lobe (all p < 0.001, and pfwe < 0.05). Of the examined perinatal risk factors, intraventricular hemorrhage grades I-II compared with no intraventricular hemorrhage and patent ductus arteriosus ligation compared with no treated patent ductus arteriosus or patent ductus arteriosus treated with ibuprofen led to volumetric differences at 10 years of age (all p < 0.001, and pfwe < 0.05). Conclusions: Children born extremely preterm exhibit volumetric alterations in a pattern overlapping that previously found at term, where many regions with differences are the main hubs of higher order networks. Some, but not all, risk factors known to be associated with structural alterations at term were associated with alterations at 10 years of age.