The developmental trajectory of 1H-MRS brain metabolites from childhood to adulthood.

Human brain development is ongoing throughout childhood, with for example, myelination of nerve fibers and refinement of synaptic connections continuing until early adulthood. 1H-Magnetic Resonance Spectroscopy (1H-MRS) can be used to quantify the concentrations of endogenous metabolites (e.g. glutamate and γ -aminobutyric acid (GABA)) in the human brain in vivo and so can provide valuable, tractable insight into the biochemical processes that support postnatal neurodevelopment. This can feasibly provide new insight into and aid the management of neurodevelopmental disorders by providing chemical markers of atypical development. This study aims to characterize the normative developmental trajectory of various brain metabolites, as measured by 1H-MRS from a midline posterior parietal voxel. We find significant non-linear trajectories for GABA+ (GABA plus macromolecules), Glx (glutamate + glutamine), total choline (tCho) and total creatine (tCr) concentrations. Glx and GABA+ concentrations steeply decrease across childhood, with more stable trajectories across early adulthood. tCr and tCho concentrations increase from childhood to early adulthood. Total N-acetyl aspartate (tNAA) and Myo-Inositol (mI) concentrations are relatively stable across development. Trajectories likely reflect fundamental neurodevelopmental processes (including local circuit refinement) which occur from childhood to early adulthood and can be associated with cognitive development; we find GABA+ concentrations significantly positively correlate with recognition memory scores.

Mind and skin: Exploring the links between inflammation, sleep disturbance and neurocognitive function in patients with atopic dermatitis.

Atopic dermatitis (AD) is a chronic, pruritic and inflammatory, dry skin condition with many known comorbidities. These include airway disease, food allergies, atopic eye disease and autoimmune conditions. Furthermore, there is often significant sleep disturbance as well as increased psychological distress and mental health problems. Severe AD therefore often has a significant impact on the quality of life of both patients and their families. In this review we discuss recent findings on the putative links between AD, its association with itch, sleep disturbance and neuropsychiatric morbidity, including the role of inflammation in these conditions. Itch was thought to predominantly drive sleep disruption in AD. We now understand changes in sleep influence immune cell distribution and the associated inflammatory cytokines, which suggests a bidirectional relationship between AD and sleep. We also increasingly recognize inflammation as a key driver in psychological symptoms and disorders. The link between cutaneous, systemic and possible brain inflammation could at least in part be driven by the sleep deprivation and itch-driven neuronal proliferation seen in AD.

Development of neonatal brain functional centrality and alterations associated with preterm birth.

Formation of the functional connectome in early life underpins future learning and behavior. However, our understanding of how the functional organization of brain regions into interconnected hubs (centrality) matures in the early postnatal period is limited, especially in response to factors associated with adverse neurodevelopmental outcomes such as preterm birth. We characterized voxel-wise functional centrality (weighted degree) in 366 neonates from the Developing Human Connectome Project. We tested the hypothesis that functional centrality matures with age at scan in term-born babies and is disrupted by preterm birth. Finally, we asked whether neonatal functional centrality predicts general neurodevelopmental outcomes at 18 months. We report an age-related increase in functional centrality predominantly within visual regions and a decrease within the motor and auditory regions in term-born infants. Preterm-born infants scanned at term equivalent age had higher functional centrality predominantly within visual regions and lower measures in motor regions. Functional centrality was not related to outcome at 18 months old. Thus, preterm birth appears to affect functional centrality in regions undergoing substantial development during the perinatal period. Our work raises the question of whether these alterations are adaptive or disruptive and whether they predict neurodevelopmental characteristics that are more subtle or emerge later in life.

Functional assessment of brain development in fetuses that subsequently deliver very preterm: An MRI pilot study.

OBJECTIVES: To evaluate changes occurring in the fetal brain prior to very preterm delivery using MRI T2* relaxometry, an indirect assessment of tissue perfusion. METHOD: Fetuses that subsequently delivered spontaneously <32 weeks gestation and a control cohort were identified from pre-existing datasets. Participants had undergone a 3T MRI assessment including T2* relaxometry of the fetal brain using a 2D multi-slice gradient echo single shot echo planar imaging sequence. T2* maps were generated, supratentorial brain tissue was manually segmented and mean T2* values were generated. Groups were compared using quadratic regression. RESULTS: Twenty five fetuses that subsequently delivered <32 weeks and 67 that delivered at term were included. Mean gestation at MRI was 24.5 weeks (SD 3.3) and 25.4 weeks (SD 3.1) and gestation at delivery 25.5 weeks (SD 3.4) and 39.7 weeks (SD 1.2) in the preterm and term cohorts respectively. Brain mean T2* values were significantly lower in fetuses that subsequently delivered before 32 weeks gestation (p < 0.001). CONCLUSION: Alterations in brain maturation appear to occur prior to preterm delivery. Further work is required to explore these associations, but these findings suggest a potential window for therapeutic neuroprotective agents in fetuses at high risk of preterm delivery in the future.

Development of human white matter pathways in utero over the second and third trimester.

During the second and third trimesters of human gestation, rapid neurodevelopment is underpinned by fundamental processes including neuronal migration, cellular organization, cortical layering, and myelination. In this time, white matter growth and maturation lay the foundation for an efficient network of structural connections. Detailed knowledge about this developmental trajectory in the healthy human fetal brain is limited, in part, due to the inherent challenges of acquiring high-quality MRI data from this population. Here, we use state-of-the-art high-resolution multishell motion-corrected diffusion-weighted MRI (dMRI), collected as part of the developing Human Connectome Project (dHCP), to characterize the in utero maturation of white matter microstructure in 113 fetuses aged 22 to 37 wk gestation. We define five major white matter bundles and characterize their microstructural features using both traditional diffusion tensor and multishell multitissue models. We found unique maturational trends in thalamocortical fibers compared with association tracts and identified different maturational trends within specific sections of the corpus callosum. While linear maturational increases in fractional anisotropy were seen in the splenium of the corpus callosum, complex nonlinear trends were seen in the majority of other white matter tracts, with an initial decrease in fractional anisotropy in early gestation followed by a later increase. The latter is of particular interest as it differs markedly from the trends previously described in ex utero preterm infants, suggesting that this normative fetal data can provide significant insights into the abnormalities in connectivity which underlie the neurodevelopmental impairments associated with preterm birth.

In vivo T1 mapping of neonatal brain tissue at 64 mT.

PURPOSE: Ultralow-field (ULF) point-of-care MRI systems allow image acquisition without interrupting medical provision, with neonatal clinical care being an important potential application. The ability to measure neonatal brain tissue T1 is a key enabling technology for subsequent structural image contrast optimization, as well as being a potential biomarker for brain development. Here we describe an optimized strategy for neonatal T1 mapping at ULF. METHODS: Examinations were performed on a 64-mT portable MRI system. A phantom validation experiment was performed, and a total of 33 in vivo exams were acquired from 28 neonates with postmenstrual age ranging from 31+4 to 49+0  weeks. Multiple inversion-recovery turbo spin-echo sequences were acquired with differing inversion and repetition times. An analysis pipeline incorporating inter-sequence motion correction generated proton density and T1 maps. Regions of interest were placed in the cerebral deep gray matter, frontal white matter, and cerebellum. Weighted linear regression was used to predict T1 as a function of postmenstrual age. RESULTS: Reduction of T1 with postmenstrual age is observed in all measured brain tissue; the change in T1 per week and 95% confidence intervals is given by dT1  = -21 ms/week [-25, -16] (cerebellum), dT1  = -14 ms/week [-18, -10] (deep gray matter), and dT1  = -35 ms/week [-45, -25] (white matter). CONCLUSION: Neonatal T1 values at ULF are shorter than those previously described at standard clinical field strengths, but longer than those of adults at ULF. T1 reduces with postmenstrual age and is therefore a candidate biomarker for perinatal brain development.

Predicting age and clinical risk from the neonatal connectome.

The development of perinatal brain connectivity underpins motor, cognitive and behavioural abilities in later life. Diffusion MRI allows the characterisation of subtle inter-individual differences in structural brain connectivity. Individual brain connectivity maps (connectomes) are by nature high in dimensionality and complex to interpret. Machine learning methods are a powerful tool to uncover properties of the connectome which are not readily visible and can give us clues as to how and why individual developmental trajectories differ. In this manuscript we used Deep Neural Networks and Random Forests to predict demographic and neurodevelopmental characteristics from neonatal structural connectomes in a large sample of babies (n = 524) from the developing Human Connectome Project. We achieved an accurate prediction of post menstrual age (PMA) at scan in term-born infants (mean absolute error (MAE) = 0.72 weeks, r = 0.83 and p < 0.001). We also achieved good accuracy when predicting gestational age at birth in a cohort of term and preterm babies scanned at term equivalent age (MAE = 2.21 weeks, r = 0.82, p < 0.001). We subsequently used sensitivity analysis to obtain feature relevance from our prediction models, with the most important connections for prediction of PMA and GA found to predominantly involve frontal and temporal regions, thalami, and basal ganglia. From our models of PMA at scan for infants born at term, we computed a brain maturation index (predicted age minus actual age) of individual preterm neonates and found a significant correlation between this index and motor outcome at 18 months corrected age. Our results demonstrate the applicability of machine learning techniques in analyses of the neonatal connectome and suggest that a neural substrate of brain maturation with implications for future neurodevelopment is detectable at term equivalent age from the neonatal connectome.

Development of functional organization within the sensorimotor network across the perinatal period.

In the mature human brain, the neural processing related to different body parts is reflected in patterns of functional connectivity, which is strongest between functional homologs in opposite cortical hemispheres. To understand how this organization is first established, we investigated functional connectivity between limb regions in the sensorimotor cortex in 400 preterm and term infants aged across the equivalent period to the third trimester of gestation (32-45 weeks postmenstrual age). Masks were obtained from empirically derived functional responses in neonates from an independent data set. We demonstrate the early presence of a crude but spatially organized functional connectivity, that rapidly matures across the preterm period to achieve an adult-like configuration by the normal time of birth. Specifically, connectivity was strongest between homolog regions, followed by connectivity between adjacent regions (different limbs but same hemisphere) already in the preterm brain, and increased with age. These changes were specific to the sensorimotor network. Crucially, these trajectories were strongly dependent on age more than age of birth. This demonstrates that during the perinatal period the sensorimotor cortex undergoes preprogrammed changes determining the functional movement organization that are not altered by preterm birth in absence of brain injury.

Effects of gestational age at birth on perinatal structural brain development in healthy term-born babies.

Infants born in early term (37-38 weeks gestation) experience slower neurodevelopment than those born at full term (40-41 weeks gestation). While this could be due to higher perinatal morbidity, gestational age at birth may also have a direct effect on the brain. Here we characterise brain volume and white matter correlates of gestational age at birth in healthy term-born neonates and their relationship to later neurodevelopmental outcome using T2 and diffusion weighted MRI acquired in the neonatal period from a cohort (n = 454) of healthy babies born at term age (>37 weeks gestation) and scanned between 1 and 41 days after birth. Images were analysed using tensor-based morphometry and tract-based spatial statistics. Neurodevelopment was assessed at age 18 months using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Infants born earlier had higher relative ventricular volume and lower relative brain volume in the deep grey matter, cerebellum and brainstem. Earlier birth was also associated with lower fractional anisotropy, higher mean, axial, and radial diffusivity in major white matter tracts. Gestational age at birth was positively associated with all Bayley-III subscales at age 18 months. Regression models predicting outcome from gestational age at birth were significantly improved after adding neuroimaging features associated with gestational age at birth. This work adds to the body of evidence of the impact of early term birth and highlights the importance of considering the effect of gestational age at birth in future neuroimaging studies including term-born babies.

The Developing Human Connectome Project: typical and disrupted perinatal functional connectivity.

The Developing Human Connectome Project is an Open Science project that provides the first large sample of neonatal functional MRI data with high temporal and spatial resolution. These data enable mapping of intrinsic functional connectivity between spatially distributed brain regions under normal and adverse perinatal circumstances, offering a framework to study the ontogeny of large-scale brain organization in humans. Here, we characterize in unprecedented detail the maturation and integrity of resting state networks (RSNs) at term-equivalent age in 337 infants (including 65 born preterm). First, we applied group independent component analysis to define 11 RSNs in term-born infants scanned at 43.5-44.5 weeks postmenstrual age (PMA). Adult-like topography was observed in RSNs encompassing primary sensorimotor, visual and auditory cortices. Among six higher-order, association RSNs, analogues of the adult networks for language and ocular control were identified, but a complete default mode network precursor was not. Next, we regressed the subject-level datasets from an independent cohort of infants scanned at 37-43.5 weeks PMA against the group-level RSNs to test for the effects of age, sex and preterm birth. Brain mapping in term-born infants revealed areas of positive association with age across four of six association RSNs, indicating active maturation in functional connectivity from 37 to 43.5 weeks PMA. Female infants showed increased connectivity in inferotemporal regions of the visual association network. Preterm birth was associated with striking impairments of functional connectivity across all RSNs in a dose-dependent manner; conversely, connectivity of the superior parietal lobules within the lateral motor network was abnormally increased in preterm infants, suggesting a possible mechanism for specific difficulties such as developmental coordination disorder, which occur frequently in preterm children. Overall, we found a robust, modular, symmetrical functional brain organization at normal term age. A complete set of adult-equivalent primary RSNs is already instated, alongside emerging connectivity in immature association RSNs, consistent with a primary-to-higher order ontogenetic sequence of brain development. The early developmental disruption imposed by preterm birth is associated with extensive alterations in functional connectivity.

Edited magnetic resonance spectroscopy in the neonatal brain.

J-difference-edited spectroscopy is a valuable approach for the detection of low-concentration metabolites with magnetic resonance spectroscopy (MRS). Currently, few edited MRS studies are performed in neonates due to suboptimal signal-to-noise ratio, relatively long acquisition times, and vulnerability to motion artifacts. Nonetheless, the technique presents an exciting opportunity in pediatric imaging research to study rapid maturational changes of neurotransmitter systems and other metabolic systems in early postnatal life. Studying these metabolic processes is vital to understanding the widespread and rapid structural and functional changes that occur in the first years of life. The overarching goal of this review is to provide an introduction to edited MRS for neonates, including the current state-of-the-art in editing methods and editable metabolites, as well as to review the current literature applying edited MRS to the neonatal brain. Existing challenges and future opportunities, including the lack of age-specific reference data, are also discussed.

Neurodisability care in the time of COVID-19.

BACKGROUND: The COVID-19 pandemic resulted in an unprecedented societal and healthcare global crisis. Associated changes in regular healthcare provision and lifestyle through societal lockdown are likely to have affected clinical management and well-being of children/young people with neurodisability, who often require complex packages of multidisciplinary care. METHODS: We surveyed 108 families of children/young people with severe physical neurodisability and multiple comorbidities to understand how the pandemic had affected acute clinical status, routine healthcare provision, schooling and family mental and social well-being. RESULTS: A significant proportion of families reported missing hospital appointments and routine therapy, with subsequent worsening of symptoms and function. Families additionally described worsening stress and anxiety during the pandemic, regardless of their baseline level of socio-economic deprivation. CONCLUSION: This highlights the profound effect of the COVID-19 pandemic on health and function in young people with severe neurodisabilities and emphasizes the clear need to better understand how to support this vulnerable population moving forwards.

Care in COVID: A qualitative analysis of the impact of COVID-19 on the health and care of children and young people with severe physical neurodisability and their families.

AIM: To evaluate clinicians' perspectives on the impact of 'lockdown' during the COVID-19 pandemic for children and young people with severe physical neurodisability and their families. METHOD: Framework analysis of comments from families during a recent service review was used to code the themes discussed according to the World Health Organization International Classification of Functioning, Disability and Health (ICF) and interpreted into emergent themes to summarize the impact of lockdown (Stage 1). They were presented to a clinician focus group for discussion (consultants and physiotherapists working in a specialist motor disorders service, [Stage 2]). RESULTS: Three overarching themes 'Uncertainty and Anxiety', 'Exacerbation of Existing Inequalities' and 'Care Provision: Reaction, Adaptation, and Innovation' summed up the impact of the COVID-19 pandemic on health and well-being in children and young people with neurodisability and their families. All themes were influenced by time. INTERPRETATION: This study reflects clinician's perceptions of family experiences of the pandemic and lockdown. Significant impact is apparent in the entire U.K. population, but the complexity of care needs for children with physical neurodisability exacerbates this. Lobbying for government policy is vital to ensure that all children, and in particular those with significant health and social care needs, are protected and continue to access services. During the restoration and recovery phase of the pandemic, there is a need for service reconfiguration that utilizes what we have learned and is adaptive to individual family circumstances.

Simultaneous quantification of GABA, Glx and GSH in the neonatal human brain using magnetic resonance spectroscopy.

Balance between inhibitory and excitatory neurotransmitter systems and the protective role of the major antioxidant glutathione (GSH) are central to early healthy brain development. Disruption has been implicated in the early life pathophysiology of psychiatric disorders and neurodevelopmental conditions including Autism Spectrum Disorder. Edited magnetic resonance spectroscopy (MRS) methods such as HERMES have great potential for providing important new non-invasive insights into these crucial processes in human infancy. In this work, we describe a systematic approach to minimise the impact of specific technical challenges inherent to acquiring MRS data in a neonatal population, including automatic segmentation, full tissue-correction and optimised GABA+ fitting and consider the minimum requirements for a robust edited-MRS acquisition. With this approach we report for the first time simultaneous GABA+, Glx (glutamate + glutamine) and GSH concentrations in the neonatal brain (n = 18) in two distinct regions (thalamus and anterior cingulate cortex (ACC)) using edited MRS at 3T. The improved sensitivity provided by our method allows specific regional neurochemical differences to be identified including: significantly lower Glx and GSH ratios to total creatine in the thalamus compared to the ACC (p < 0.001 for both), and significantly higher GSH levels in the ACC following tissue-correction (p < 0.01). Furthermore, in contrast to adult GABA+ which can typically be accurately fitted with a single peak, all neonate spectra displayed a characteristic doublet GABA+ peak at 3 ppm, indicating a lower macromolecule (MM) contribution to the 3 ppm signal in neonates. Relatively high group-level variance shows the need to maximise voxel size/acquisition time in edited neonatal MRS acquisitions for robust estimation of metabolites. Application of this method to study how these levels and balance are altered by early-life brain injury or genetic risk can provide important new knowledge about the pathophysiology underlying neurodevelopmental disorders.

Construction and validation of a database of head models for functional imaging of the neonatal brain.

The neonatal brain undergoes dramatic structural and functional changes over the last trimester of gestation. The accuracy of source localisation of brain activity recorded from the scalp therefore relies on accurate age-specific head models. Although an age-appropriate population-level atlas could be used, detail is lost in the construction of such atlases, in particular with regard to the smoothing of the cortical surface, and so such a model is not representative of anatomy at an individual level. In this work, we describe the construction of a database of individual structural priors of the neonatal head using 215 individual-level datasets at ages 29-44 weeks postmenstrual age from the Developing Human Connectome Project. We have validated a method to segment the extra-cerebral tissue against manual segmentation. We have also conducted a leave-one-out analysis to quantify the expected spatial error incurred with regard to localising functional activation when using a best-matching individual from the database in place of a subject-specific model; the median error was calculated to be 8.3 mm (median absolute deviation 3.8 mm). The database can be applied for any functional neuroimaging modality which requires structural data whereby the physical parameters associated with that modality vary with tissue type and is freely available at www.ucl.ac.uk/dot-hub.

The developing Human Connectome Project (dHCP) automated resting-state functional processing framework for newborn infants.

The developing Human Connectome Project (dHCP) aims to create a detailed 4-dimensional connectome of early life spanning 20-45 weeks post-menstrual age. This is being achieved through the acquisition of multi-modal MRI data from over 1000 in- and ex-utero subjects combined with the development of optimised pre-processing pipelines. In this paper we present an automated and robust pipeline to minimally pre-process highly confounded neonatal resting-state fMRI data, robustly, with low failure rates and high quality-assurance. The pipeline has been designed to specifically address the challenges that neonatal data presents including low and variable contrast and high levels of head motion. We provide a detailed description and evaluation of the pipeline which includes integrated slice-to-volume motion correction and dynamic susceptibility distortion correction, a robust multimodal registration approach, bespoke ICA-based denoising, and an automated QC framework. We assess these components on a large cohort of dHCP subjects and demonstrate that processing refinements integrated into the pipeline provide substantial reduction in movement related distortions, resulting in significant improvements in SNR, and detection of high quality RSNs from neonates.

An fMRI Compatible Smart Device for Measuring Palmar Grasping Actions in Newborns.

Grasping is one of the first dominant motor behaviors that enable interaction of a newborn infant with its surroundings. Although atypical grasping patterns are considered predictive of neuromotor disorders and injuries, their clinical assessment suffers from examiner subjectivity, and the neuropathophysiology is poorly understood. Therefore, the combination of technology with functional magnetic resonance imaging (fMRI) may help to precisely map the brain activity associated with grasping and thus provide important insights into how functional outcomes can be improved following cerebral injury. This work introduces an MR-compatible device (i.e., smart graspable device (SGD)) for detecting grasping actions in newborn infants. Electromagnetic interference immunity (EMI) is achieved using a fiber Bragg grating sensor. Its biocompatibility and absence of electrical signals propagating through the fiber make the safety profile of the SGD particularly favorable for use with fragile infants. Firstly, the SGD design, fabrication, and metrological characterization are described, followed by preliminary assessments on a preterm newborn infant and an adult during an fMRI experiment. The results demonstrate that the combination of the SGD and fMRI can safely and precisely identify the brain activity associated with grasping behavior, which may enable early diagnosis of motor impairment and help guide tailored rehabilitation programs.

New approaches to studying early brain development in Down syndrome.

Down syndrome is the most common genetic developmental disorder in humans and is caused by partial or complete triplication of human chromosome 21 (trisomy 21). It is a complex condition which results in multiple lifelong health problems, including varying degrees of intellectual disability and delays in speech, memory, and learning. As both length and quality of life are improving for individuals with Down syndrome, attention is now being directed to understanding and potentially treating the associated cognitive difficulties and their underlying biological substrates. These have included imaging and postmortem studies which have identified decreased regional brain volumes and histological anomalies that accompany early onset dementia. In addition, advances in genome-wide analysis and Down syndrome mouse models are providing valuable insight into potential targets for intervention that could improve neurogenesis and long-term cognition. As little is known about early brain development in human Down syndrome, we review recent advances in magnetic resonance imaging that allow non-invasive visualization of brain macro- and microstructure, even in utero. It is hoped that together these advances may enable Down syndrome to become one of the first genetic disorders to be targeted by antenatal treatments designed to 'normalize' brain development. WHAT THIS PAPER ADDS: Magnetic resonance imaging can provide non-invasive characterization of early brain development in Down syndrome. Down syndrome mouse models enable study of underlying pathology and potential intervention strategies. Potential therapies could modify brain structure and improve early cognitive levels. Down syndrome may be the first genetic disorder to have targeted therapies which alter antenatal brain development.

NUEVOS ENFOQUES PARA ESTUDIAR EL DESARROLLO CEREBRAL TEMPRANO EN EL SÍNDROME DE DOWN: El síndrome de Down es el trastorno del desarrollo genético más común en los seres humanos y es causado por la triplicación parcial o completa del cromosoma 21 (trisomía 21). Es una condición compleja que se traduce en múltiples problemas de salud a lo largo de toda la vida, incluidos diversos grados de discapacidad intelectual y retrasos en el habla, la memoria y el aprendizaje. Debido a que la duración y la calidad de vida están mejorando para las personas con síndrome de Down, ahora se está prestando atención a la comprensión y al tratamiento de las dificultades cognitivas asociadas y sus sustratos biológicos subyacentes. Estos estudios han incluido estudios de imagen y postmortem que han identificado volúmenes cerebrales regionales disminuidos y anomalías histológicas que acompañan a la demencia de inicio temprano. Además, los avances en el análisis del genoma completo y los modelos de ratones con síndrome de Down brindan información valiosa sobre los posibles objetivos de la intervención que podrían mejorar la neurogénesis y la cognición a largo plazo. Como se sabe poco sobre el desarrollo temprano del cerebro en el síndrome de Down humano, revisamos los avances recientes en imágenes de resonancia magnética que permiten la visualización no invasiva de la macro y microestructura cerebral, incluso en el útero. Se espera que, en conjunto, estos avances puedan permitir que el síndrome de Down se convierta en uno de los primeros trastornos genéticos a los que se aplican tratamientos prenatales diseñados para "encauzar" el desarrollo cerebral.

NOVAS ABORDAGENS PARA O ESTUDO DE DESENVOLVIMENTO CEREBRAL PRECOCE NA SÍNDROME DE DOWN: A síndrome de Down é a desordem desenvolvimental de origem genética mais comum em humanos. É causada por triplicação parcial ou completa do cromossomo 21 (trissomia do 21). Trata-se de uma condição complexa que resulta em múltiplos problemas de saúde ao longo da vida, incluindo graus variados de deficiência intelectual, e atrasos na fala, memória e aprendizagem. Como tanto a duração quanto a qualidade de vida têm melhorado para indivíduos com síndrome de Down, agora a atenção se volta para compreender e potencialmente tratar dificuldades cognitivas associadas e seus substratos biológicos de base. Incluem-se estudos de imagem e pós-morte que identificaram menores volumes cerebrais e anomalias histológicas que acompanham a demência de início precoe. Além disso, avanços na análise do genoma em modelos de ratos com síndrome de Down fornecem informações valiosas sobre potenciais alvos para intervenção que podem melhorar a neurogênese e a cognição em longo prazo. Como pouco se sabe sobre o desenvolvimento cerebral precoce na síndrome de Down, nós revisamos avanços recentes em imagens por ressonância magnética que permitem visualização não-invasiva da macro- e micro-estrutura do cérebro, mesmo no útero. Espera-se que, juntos, estes avanços possibilitem que a síndrome de Down se torne a primeira desorgem genética a ser alvo de tratamentos antenatais voltados para "normalizar" o desenvolvimento cerebral.

Anticoagulation in the management of neonatal cerebral sinovenous thrombosis: a systematic review and meta-analysis.

AIM: To determine whether anticoagulation therapy (ACT) in the treatment of neonatal cerebral sinovenous thrombosis (CSVT) improves outcomes, in the presence or absence of pre-existing intracerebral haemorrhage (ICH). METHOD: We searched CENTRAL, MEDLINE, Embase, CINAHL, the Web of Science, and clinical trial databases. We considered data from retrospective and prospective cohort studies, case series, and randomized controlled studies evaluating outcomes of CSVT treated with anticoagulation or no anticoagulation. Studies were included if they involved infants either younger than 28 days of age or younger than 44 weeks postmenstrual age at the time of diagnosis of CSVT in which ACT was considered. RESULTS: Seven non-randomized studies were included in meta-analysis. ACT had no significant effect on mortality before discharge either in the presence or absence of pre-existing ICH, nor on the incidence of extension of pre-existing ICH. ACT was associated with a reduced risk of propagation of thrombus (risk ratio 0.14, 95% confidence interval 0.03-0.72). INTERPRETATION: There are no randomized trials assessing the safety and efficacy of ACT in the treatment of neonatal CSVT. The results of this meta-analysis would justify a position of equipoise and support the need for well-designed randomized controlled trials of ACT in this population. WHAT THIS PAPER ADDS: No randomized studies have evaluated anticoagulation therapy (ACT) in neonatal cerebral sinovenous thrombosis. ACT may reduce thrombus propagation. No evidence of increased morbidity or mortality with ACT was demonstrated. A position of equipoise is justified, supporting the need for placebo-controlled randomized trials.

Specialization and integration of functional thalamocortical connectivity in the human infant.

Connections between the thalamus and cortex develop rapidly before birth, and aberrant cerebral maturation during this period may underlie a number of neurodevelopmental disorders. To define functional thalamocortical connectivity at the normal time of birth, we used functional MRI (fMRI) to measure blood oxygen level-dependent (BOLD) signals in 66 infants, 47 of whom were at high risk of neurocognitive impairment because of birth before 33 wk of gestation and 19 of whom were term infants. We segmented the thalamus based on correlation with functionally defined cortical components using independent component analysis (ICA) and seed-based correlations. After parcellating the cortex using ICA and segmenting the thalamus based on dominant connections with cortical parcellations, we observed a near-facsimile of the adult functional parcellation. Additional analysis revealed that BOLD signal in heteromodal association cortex typically had more widespread and overlapping thalamic representations than primary sensory cortex. Notably, more extreme prematurity was associated with increased functional connectivity between thalamus and lateral primary sensory cortex but reduced connectivity between thalamus and cortex in the prefrontal, insular and anterior cingulate regions. This work suggests that, in early infancy, functional integration through thalamocortical connections depends on significant functional overlap in the topographic organization of the thalamus and that the experience of premature extrauterine life modulates network development, altering the maturation of networks thought to support salience, executive, integrative, and cognitive functions.