Updates to the Melbourne Children's Regional Infant Brain Software Package (M-CRIB-S).

The delineation of cortical areas on magnetic resonance images (MRI) is important for understanding the complexities of the developing human brain. The previous version of the Melbourne Children's Regional Infant Brain (M-CRIB-S) (Adamson et al. Scientific Reports, 10(1), 10, 2020) is a software package that performs whole-brain segmentation, cortical surface extraction and parcellation of the neonatal brain. Available cortical parcellation schemes in the M-CRIB-S are the adult-compatible 34- and 31-region per hemisphere Desikan-Killiany (DK) and Desikan-Killiany-Tourville (DKT), respectively. We present a major update to the software package which achieves two aims: 1) to make the voxel-based segmentation outputs derived from the Freesurfer-compatible M-CRIB scheme, and 2) to improve the accuracy of whole-brain segmentation and cortical surface extraction. Cortical surface extraction has been improved with additional steps to improve penetration of the inner surface into thin gyri. The improved cortical surface extraction is shown to increase the robustness of measures such as surface area, cortical thickness, and cortical volume.

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.

Midsagittal corpus callosal thickness and cognitive impairment in Parkinson's disease.

People diagnosed with Parkinson's disease (PD) can experience significant neuropsychiatric symptoms, including cognitive impairment and dementia, the neuroanatomical substrates of which are not fully characterised. Symptoms associated with cognitive impairment and dementia in PD may relate to direct structural changes to the corpus callosum via primary white matter pathology or as a secondary outcome due to the degeneration of cortical regions. Using magnetic resonance imaging, the corpus callosum can be investigated at the midsagittal plane, where it converges to a contiguous mass and is not intertwined with other tracts. The objective of this project was thus twofold: First, we investigated possible changes in the thickness of the midsagittal callosum and cortex in patients with PD with varying levels of cognitive impairment; and secondly, we investigated the relationship between the thickness of the midsagittal corpus callosum and the thickness of the cortex. Study participants included cognitively unimpaired PD participants (n = 35), PD participants with mild cognitive impairment (n = 22), PD participants with dementia (n = 17) and healthy controls (n = 27). We found thinning of the callosum in PD-related dementia compared with PD-related mild cognitive impairment and cognitively unimpaired PD participants. Regression analyses found thickness of the left medial orbitofrontal cortex to be positively correlated with thickness of the anterior callosum in PD-related mild cognitive impairment. This study suggests that a midsagittal thickness model can uncover changes to the corpus callosum in PD-related dementia, which occur in line with changes to the cortex in this advanced disease stage.

Global transcriptomic analysis of a murine osteocytic cell line subjected to spaceflight.

Bone loss is a major health concern for astronauts during long-term spaceflight and for patients during prolonged bed rest or paralysis. Growing evidence suggests that osteocytes, the most abundant cells in the mineralized bone matrix, play a key role in sensing mechanical forces applied to the skeleton and integrating the orchestrated response into subcellular biochemical signals to modulate bone homeostasis. However, the precise molecular mechanisms underlying both mechanosensation and mechanotransduction in late-osteoblast-to-osteocyte cells under microgravity (µG) have yet to be elucidated. To unravel the mechanisms by which late osteoblasts and osteocytes sense and respond to mechanical unloading, we exposed the osteocytic cell line, Ocy454, to 2, 4, or 6 days of µG on the SpaceX Dragon-6 resupply mission to the International Space Station. Our results showed that µG impairs the differentiation of osteocytes, consistent with prior osteoblast spaceflight experiments, which resulted in the downregulation of key osteocytic genes. Importantly, we demonstrate the modulation of critical glycolysis pathways in osteocytes subjected to microgravity and discovered a set of mechanical sensitive genes that are consistently regulated in multiple cell types exposed to microgravity suggesting a common, yet to be fully elucidated, genome-wide response to microgravity. Ground-based simulated microgravity experiments utilizing the NASA rotating-wall-vessel were unable to adequately replicate the changes in microgravity exposure highlighting the importance of spaceflight missions to understand the unique environmental stress that microgravity presents to diverse cell types. In summary, our findings demonstrate that osteocytes respond to µG with an increase in glucose metabolism and oxygen consumption.

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.

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.

Parcellation of the neonatal cortex using Surface-based Melbourne Children's Regional Infant Brain atlases (M-CRIB-S).

Longitudinal studies measuring changes in cortical morphology over time are best facilitated by parcellation schemes compatible across all life stages. The Melbourne Children's Regional Infant Brain (M-CRIB) and M-CRIB 2.0 atlases provide voxel-based parcellations of the cerebral cortex compatible with the Desikan-Killiany (DK) and the Desikan-Killiany-Tourville (DKT) cortical labelling schemes. This study introduces surface-based versions of the M-CRIB and M-CRIB 2.0 atlases, termed M-CRIB-S(DK) and M-CRIB-S(DKT), with a pipeline for automated parcellation utilizing FreeSurfer and developing Human Connectome Project (dHCP) tools. Using T2-weighted magnetic resonance images of healthy neonates (n = 58), we created average spherical templates of cortical curvature and sulcal depth. Manually labelled regions in a subset (n = 10) were encoded into the spherical template space to construct M-CRIB-S(DK) and M-CRIB-S(DKT) atlases. Labelling accuracy was assessed using Dice overlap and boundary discrepancy measures with leave-one-out cross-validation. Cross-validated labelling accuracy was high for both atlases (average regional Dice = 0.79-0.83). Worst-case boundary discrepancy instances ranged from 9.96-10.22 mm, which appeared to be driven by variability in anatomy for some cases. The M-CRIB-S atlas data and automatic pipeline allow extraction of neonatal cortical surfaces labelled according to the DK or DKT parcellation schemes.

Tracking regional brain growth up to age 13 in children born term and very preterm.

Serial regional brain growth from the newborn period to adolescence has not been described. Here, we measured regional brain growth in 216 very preterm (VP) and 45 full-term (FT) children. Brain MRI was performed at term-equivalent age, 7 and 13 years in 82 regions. Brain volumes increased between term-equivalent and 7 years, with faster growth in the FT than VP group. Perinatal brain abnormality was associated with less increase in brain volume between term-equivalent and 7 years in the VP group. Between 7 and 13 years, volumes were relatively stable, with some subcortical and cortical regions increasing while others reduced. Notably, VP infants continued to lag, with overall brain size generally less than that of FT peers at 13 years. Parieto-frontal growth, mainly between 7 and 13 years in FT children, was associated with higher intelligence at 13 years. This study improves understanding of typical and atypical regional brain growth.

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.

Quantifying individual differences in brain morphometry underlying symptom severity in Autism Spectrum Disorders.

The neurobiology of heterogeneous neurodevelopmental disorders such as autism spectrum disorders (ASD) are still unclear. Despite extensive efforts, most findings are difficult to reproduce due to high levels of individual variance in phenotypic expression. To quantify individual differences in brain morphometry in ASD, we implemented a novel subject-level, distance-based method on subject-specific attributes. In a large multi-cohort sample, each subject with ASD (n = 100; n = 84 males; mean age: 11.43 years; mean IQ: 110.58) was strictly matched to a control participant (n = 100; n = 84 males; mean age: 11.43 years; mean IQ: 110.70). Intrapair Euclidean distance of MRI brain morphometry and symptom severity measures (Social Responsiveness Scale) were entered into a regularised machine learning pipeline for feature selection, with rigorous out-of-sample validation and permutation testing. Subject-specific structural morphometry features significantly predicted individual variation in ASD symptom severity (19 cortical thickness features, p = 0.01, n = 5000 permutations; 10 surface area features, p = 0.006, n = 5000 permutations). Findings remained robust across subjects and were replicated in validation samples. Identified cortical regions implicate key hubs of the salience and default mode networks as neuroanatomical features of social impairment in ASD. Present results highlight the importance of subject-level markers in ASD, and offer an important step forward in understanding the neurobiology of heterogeneous disorders.

Desikan-Killiany-Tourville Atlas Compatible Version of M-CRIB Neonatal Parcellated Whole Brain Atlas: The M-CRIB 2.0.

Our recently published M-CRIB atlas comprises 100 neonatal brain regions including 68 compatible with the widely-used Desikan-Killiany adult cortical atlas. A successor to the Desikan-Killiany atlas is the Desikan-Killiany-Tourville atlas, in which some regions with unclear boundaries were removed, and many existing boundaries were revised to conform to clearer landmarks in sulcal fundi. Our first aim here was to modify cortical M-CRIB regions to comply with the Desikan-Killiany-Tourville protocol, in order to offer: (a) compatibility with this adult cortical atlas, (b) greater labeling accuracy due to clearer landmarks, and (c) optimisation of cortical regions for integration with surface-based infant parcellation pipelines. Secondly, we aimed to update subcortical regions in order to offer greater compatibility with subcortical segmentations produced in FreeSurfer. Data utilized were the T2-weighted MRI scans in our M-CRIB atlas, for 10 healthy neonates (post-menstrual age at MRI 40-43 weeks, four female), and corresponding parcellated images. Edits were performed on the parcellated images in volume space using ITK-SNAP. Cortical updates included deletion of frontal and temporal poles and 'Banks STS,' and modification of boundaries of many other regions. Changes to subcortical regions included the addition of 'ventral diencephalon,' and deletion of 'subcortical matter' labels. A detailed updated parcellation protocol was produced. The resulting whole-brain M-CRIB 2.0 atlas comprises 94 regions altogether. This atlas provides comparability with adult Desikan-Killiany-Tourville-labeled cortical data and FreeSurfer-labeed subcortical data, and is more readily adaptable for incorporation into surface-based neonatal parcellation pipelines. As such, it offers the ability to help facilitate a broad range of investigations into brain structure and function both at the neonatal time point and developmentally across the lifespan.

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.

Efficiency of structural connectivity networks relates to intrinsic motivation in children born extremely preterm.

Intrinsic motivation is essential for academic success and cognitive growth, but limited work has examined the neuroanatomical underpinnings of intrinsic motivation from a network perspective, particularly in early childhood. Using graph theoretical analysis, this study investigated global and local properties of structural connectivity networks in relation to intrinsic motivation within a vulnerable group of children at early school age. Fifty-three 7 year-old children born extremely preterm (<28 weeks' gestational age)/extremely low birth weight (<1000 g) underwent T1 and diffusion weighted imaging. Structural connectivity networks were generated using 162 cortical and subcortical nodes, and edges were created using constrained spherical deconvolution-based tractography. Global and node-specific network measures were analyzed in association with self-reported aspects of intrinsic motivation for school learning (Mastery, Challenge and Curiosity) using linear regression. Results indicated that increased information transfer across the network was associated with greater Mastery, while increased clustering and small-world topology related to greater Challenge. Increased efficiency and connection strength of the striatum in particular, related to greater intrinsic motivation. These findings suggest that both integrated and segregated network communication support aspects of intrinsic motivation in childhood, and shed new light on structural network properties important for intrinsic motivation orientations in extremely preterm children at early school age.

Callosal thickness profiles for prognosticating conversion from mild cognitive impairment to Alzheimer's disease: A classification approach.

INTRODUCTION: Alzheimer's disease (AD) is the most common form of dementia. Finding biomarkers to prognosticate transition from mild cognitive impairment (MCI) to AD is important to clinical medicine. Promising imaging biomarkers of AD conversion identified so far include atrophy of the cerebral cortex and subcortical gray matter nuclei. METHODS: This study introduces thickness and bending angle of the corpus callosum as a putative white matter marker of MCI to AD conversion. The corpus callosum is computationally less demanding to segment automatically compared to more complicated structures and a subject can be processed in a few minutes. We aimed to demonstrate that callosal shape and thickness measures provide a simple, effective, and accurate prognostication tool in ADNI dataset. Using longitudinal datasets, we classified MCI subjects based on conversion to AD assessed via cognitive testing. We evaluated the classification accuracy of callosal shape features in comparison with the existing "gold standard" cortical thickness and subcortical gray matter volume measures. RESULTS: The callosal thickness measures were less accurate in classifying conversion status by cognitive scores compared to gray matter measures for AD. CONCLUSIONS: While this paper presented a negative result, this method may be more suitable for a disease of the white matter.

Caffeine for apnea of prematurity and brain development at 11 years of age.

OBJECTIVE: Caffeine therapy for apnea of prematurity has been reported to improve brain white matter microstructure at term-equivalent age, but its long-term effects are unknown. This study aimed to investigate whether caffeine affects (1) brain structure at 11 years of age, and (2) brain development from term-equivalent age to 11 years of age, compared with placebo. METHODS: Preterm infants born ≤1250 g were randomly allocated to caffeine or placebo. Magnetic resonance imaging (MRI) was performed on 70 participants (33 caffeine, 37 placebo) at term-equivalent age and 117 participants (63 caffeine, 54 placebo) at 11 years of age. Global and regional brain volumes and white matter microstructure were measured at both time points. RESULTS: In general, there was little evidence for differences between treatment groups in brain volumes or white matter microstructure at age 11 years. There was, however, evidence that the caffeine group had a smaller corpus callosum than the placebo group. Volumetric brain development from term-equivalent to 11 years of age was generally similar between treatment groups. However, there was evidence that caffeine was associated with slower growth of the corpus callosum, and slower decreases in axial, radial, and mean diffusivities in the white matter, particularly at the level of the centrum semiovale, over time than placebo. INTERPRETATION: This study suggests any benefits of neonatal caffeine therapy on brain structure in preterm infants weaken over time and are not clearly detectable by MRI at age 11 years, although caffeine may have long-term effects on corpus callosum development.

Brain volumetric correlates of inhibition and cognitive flexibility 16 years following childhood traumatic brain injury.

Executive functions (EFs), such as inhibition and cognitive flexibility, are essential for everyday functioning, including regulation of socially appropriate emotional responses. These skills develop during childhood and continue maturing into early adulthood. The current study aimed to investigate the very long-term impact of childhood traumatic brain injury (TBI) on inhibition and cognitive flexibility, and to examine whether global white matter is associated with these abilities. Twenty-eight young adult survivors of childhood TBI (mean age at 16-year follow-up = 21.67 years, SD = 2.70) and 16 typically developing controls (TDCs), group-matched for age, sex, and socioeconomic status, completed tests of inhibition and cognitive flexibility and underwent structural MRI. Survivors of childhood TBI did not significantly differ from TDCs on EF or white matter volume. However, the relationship between EF and white matter volume differed between survivors of TBI and TDCs. Survivors of TBI did not mimic the brain behavior relationship that characterized EF in TDCs. The inverse brain behavior relationship, exhibited by childhood TBI survivors, suggests disruptions in the whole brain underpinning EF following childhood TBI.

Modelling neuroanatomical variation during childhood and adolescence with neighbourhood-preserving embedding.

Brain development is a dynamic process with tissue-specific alterations that reflect complex and ongoing biological processes taking place during childhood and adolescence. Accurate identification and modelling of these anatomical processes in vivo with MRI may provide clinically useful imaging markers of individual variability in development. In this study, we use manifold learning to build a model of age- and sex-related anatomical variation using multiple magnetic resonance imaging metrics. Using publicly available data from a large paediatric cohort (n = 768), we apply a multi-metric machine learning approach combining measures of tissue volume, cortical area and cortical thickness into a low-dimensional data representation. We find that neuroanatomical variation due to age and sex can be captured by two orthogonal patterns of brain development and we use this model to simultaneously predict age with a mean error of 1.5-1.6 years and sex with an accuracy of 81%. We validate this model in an independent developmental cohort. We present a framework for modelling anatomical development during childhood using manifold embedding. This model accurately predicts age and sex based on image-derived markers of cerebral morphology and generalises well to independent populations.

Altered structural connectivity in ADHD: a network based analysis.

Attention deficit/hyperactivity disorder (ADHD) is increasingly being viewed as a dysfunction of distributed brain networks rather than focal abnormalities. Here we investigated the structural brain network differences in children and adolescents with ADHD and healthy controls, using graph theory metrics to describe the anatomic networks and connectivity patterns, and the Network Based Statistic (NBS) to isolate the network components that differ between the two groups. Using DWI high-angular resolution diffusion imaging ('HARDI'), whole brain tractography was conducted on 21 ADHD-combined type boys (m 13.3 ± 1.9 yrs) and 21 typically developing boys (m 14.8 ± 2.1 yrs). This study presents a comprehensive structural network investigation in ADHD covering a range of commonly used methodologies, including both streamline and probabilistic tractography, tensor and constrained spherical deconvolution (CSD) models, as well as different edge weighting methods at a range of densities and t-thresholds. Using graph metrics, ADHD was associated with local neighbourhoods that were more modular and interconnected than controls, where there was a decrease in the global, long-range connections, indicating reduced communication between local, specialised networks in ADHD. ADHD presented with a sub-network of stronger connectivity encompassing bilateral frontostriatal connections as well as left occipital, temporal, and parietal regions, of which the white matter microstructure was associated with ADHD symptom severity. Probabilistic tractography using CSD and the Hagmann weighting method produced that highest stability and most robust network differences across t-thresholds. It demonstrates topological organisation disruption in distributed neural networks in ADHD, supportive of the theory of maturation delay in ADHD.