Effect of perinatal adversity on structural connectivity of the developing brain

Globally, preterm birth (defined as birth at <37 weeks of gestation) affects around 11% of deliveries and it is closely associated with cerebral palsy, cognitive impairments and neuropsychiatric diseases in later life. Magnetic Resonance Imaging (MRI) has utility for measuring different properties of the brain during the lifespan. Specially, diffusion MRI has been used in the neonatal period to quantify the effect of preterm birth on white matter structure, which enables inference about brain development and injury. By combining information from both structural and diffusion MRI, is it possible to calculate structural connectivity of the brain. This involves calculating a model of the brain as a network to extract features of interest. The process starts by defining a series of nodes (anatomical regions) and edges (connections between two anatomical regions). Once the network is created, different types of analysis can be performed to find features of interest, thereby allowing group wise comparisons. The main frameworks/tools designed to construct the brain connectome have been developed and tested in the adult human brain. There are several differences between the adult and the neonatal brain: marked variation in head size and shape, maturational processes leading to changes in signal intensity profiles, relatively lower spatial resolution, and lower contrast between tissue classes in the T1 weighted image. All of these issues make the standard processes to construct the brain connectome very challenging to apply in the neonatal population. Several groups have studied the neonatal structural connectivity proposing several alternatives to overcome these limitations. The aim of this thesis was to optimise the different steps involved in connectome analysis for neonatal data. First, to provide accurate parcellation of the cortex a new atlas was created based on a control population of term infants; this was achieved by propagating the atlas from an adult atlas through intermediate childhood spatio-temporal atlases using image registration. After this the advanced anatomically-constrained tractography framework was adapted for the neonatal population, refined using software tools for skull-stripping, tissue segmentation and parcellation specially designed and tested for the neonatal brain. Finally, the method was used to test the effect of early nutrition, specifically breast milk exposure, on structural connectivity in preterm infants. We found that infants with higher exposure to breastmilk in the weeks after preterm birth had improved structural connectivity of developing networks and greater fractional anisotropy in major white matter fasciculi. These data also show that the benefits are dose dependent with higher exposure correlating with increased white matter connectivity. In conclusion, structural connectivity is a robust method to investigate the developing human brain. We propose an optimised framework for the neonatal brain, designed for our data and using tools developed for the neonatal brain, and apply it to test the effect of breastmilk exposure on preterm infants

Bayesian segmentation of brainstem structures in MRI

VK: Lampinen, J.In this paper we present a method to segment four brainstem structures (midbrain, pons, medulla oblongata and superior cerebellar peduncle) from 3D brain MRI scans. The segmentation method relies on a probabilistic atlas of the brainstem and its neighboring brain structures. To build the atlas, we combined a dataset of 39 scans with already existing manual delineations of the whole brainstem and a dataset of 10 scans in which the brainstem structures were manually labeled with a protocol that was specifically designed for this study. The resulting atlas can be used in a Bayesian framework to segment the brainstem structures in novel scans. Thanks to the generative nature of the scheme, the segmentation method is robust to changes in MRI contrast or acquisition hardware. Using cross validation, we show that the algorithm can segment the structures in previously unseen T1 and FLAIR scans with great accuracy (mean error under 1 mm) and robustness (no failures in 383 scans including 168 AD cases). We also indirectly evaluate the algorithm with a experiment in which we study the atrophy of the brainstem in aging. The results show that, when used simultaneously, the volumes of the midbrain, pons and medulla are significantly more predictive of age than the volume of the entire brainstem, estimated as their sum. The results also demonstrate that the method can detect atrophy patterns in the brainstem structures that have been previously described in the literature. Finally, we demonstrate that the proposed algorithm is able to detect differential effects of AD on the brainstem structures. The method will be implemented as part of the popular neuroimaging package FreeSurfer.Peer reviewe

Early Markers for Cerebral Palsy

Cerebral palsy (CP) is a term referring to a nonprogressive disease of the brain originating during the antenatal, neonatal, or early postnatal period when brain neuronal connections are still evolving. Secondary effects of spasticity on growth may, however, be progressive. There may be additional disturbances of sensation, perception, cognition, communication, and behavior. Babies who are neurologically abnormal as newborns are at increased risk of neurologic abnormality in later months and years. Being born preterm (born <37 weeks of gestation) or with a very low birth weight (weighing <1500 g/<32 weeks of gestation) or extreme low birth weight (<1000 g/<28 weeks of gestation) is associated with significant motor impairment. Which specific signs in the neonate are of greatest predictive power, what long-term disability these signs predict, and how well they predict it remain unclear? Physician’s major concern is to identify specific risk factors for severe impairment in early infancy so as to predict the developmental outcome of those children that may manifest later on with neurological deficit especially if they have perinatal insult. Parents on the other hand are also concerned about their growing infants, their development, and neurological outcome. Since cerebral palsy is a permanent disorder, early detection of signs of motor impairment is crucial to assist physicians to give close follow-up of those infants and to reassure parents whose children are normal. It has been shown that intervention may be most efficient when the plasticity of the brain is high, and an early detection of brain impairment is therefore crucial. An earlier follow-up and training program can have a positive effect of the motor development of the child with CP, in particular through prevention of limb contractions, and might make a difference in the child’s ability to handle everyday challenges. In addition, an early detection of CP gives the parents more time for adjustment and preparation. Since clinical manifestations of cerebral palsy do not emerge before a child is at least 6 months, the general movement (GM) is considered the most reliable early markers for monitoring of fetal and infant movement. Abnormal General movements and absence of the so-called fidgety movements at 3-5 months post-term carries a high risk of developing cerebral palsy. Beside a high specificity (82–99%) and sensitivity (95–100%), the assessment of the general movements (GMs) is quick, nonintrusive, and easy to acquire

Neuroimaging in Friedreich's ataxia : new approaches and clinical aplication

Orientadores: Marcondes Cavalcante França Junior, Andreia Vasconcellos FariaTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: A ataxia de Friedreich (FRDA) é a ataxia autossômica recessiva mais comum no mundo. Clinicamente, é caracterizada por início precoce, alterações sensoriais e ataxia de lenta progressão. Os estudos de imagem têm focado somente em estruturas infratentoriais, desconsiderando o envolvimento de estruturas supratentoriais, diferenças fenotípicas e duração da doença, bem como a evolução do dano neurológico. Portanto, o objetivo deste trabalho é avaliar, por meio de imagens de ressonância magnética multimodal, pacientes com ataxia de Friedreich a fim de compreender a evolução do dano encefálico, identificar o padrão de dano encefálico entre os fenótipos da doença, os sítios de depósitos de ferro extra-cerebelares e as primeiras estruturas acometidas na doença. A fim de atingir todos os objetivos, foram recrutados 25 pacientes adultos com a forma clássica da doença, 13 pacientes com início tardio e 12 pacientes pediátricos. Para quantificar a gravidade da doença foi utilizada a escala FARS. O dano estrutural de substância cinza e branca foi avaliado via imagens de ressonância magnética ponderadas em T1, T2 e DTI. Para análise de tais imagens foram utilizadas as ferramentas FreeSurfer, T1 MultiAtlas, DTI Multiatlas, SPM, SpineSeg e TBSS. As comparações de grupos revelaram comprometimento microestrutural multifocal na substância branca encefálica na FRDA, com dano extenso nos pedúnculos cerebelares, corpo caloso e tratos piramidais. Encontramos também alterações na substância cinzenta no núcleo denteado do cerebelo, tronco e córtex motor. Nós não identificamos mudanças volumétricas longitudinais, porém análises prospectivas da substância branca identificaram anormalidades microestruturais progressivas no corpo caloso, tratos piramidais e pedúnculos cerebelares superiores após um ano de seguimento. A respeito do estudo comparando o tipo clássico e o tipo tardio (cFRDA vs. LOFA), nós mostramos que ambos os fenótipos possuem um padrão de anormalidades similares, mas não idênticas. Embora sutis, as diferenças estruturais encontradas ajudam a explicar a variabilidade fenotípica entre estas duas apresentações da doença. Por exemplo, o maior dano microestrutural no trato córtico-espinhal no grupo LOFA ajuda a explicar os sinais piramidais mais exuberantes neste grupo. Não fomos capazes de identificar depósitos de ferro cerebrais nos pacientes com FRDA. Neste sentido, tais depósitos ficariam restritos somente ao núcleo denteado do cerebelo. Por fim, fomos capazes de observar que a manifestação inicial da doença, vista em pacientes pediátricos, se concentra na medula espinhal e no pedúnculo cerebelar inferiorAbstract: Friedreich¿s ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide; it is characterized by early onset, sensory abnormalities and slowly progressive ataxia. Besides that, most of neuroimaging studies have been focused only in infratentorial structures of adult patients. Furthermore, studies comparing different phenotypes of disease does not exist. Therefore, the objective of this study is to assess, using multimodal magnetic (MRI) resonance imaging, patients with Friedreich ataxia to better comprehend the progression of brain damage, to identify the pattern of damage across disease phenotypes, to identify areas with abnormal iron deposits in the brain and to characterize the structures initially damaged in early disease stages. To accomplish that, we enrolled 25 adult patients with classical FRDA, 13 patients with late-onset FRDA and 12 pediatric patients. The FARS scale was employed to quantify the disease severity. To assess the structural damage in gray and white matter, we acquired T1-weighted, T2-weighted and DTI images of the brain. To evaluate these images, we used the following tools: FreeSurfer, T1 MultiAtlas, SPM, DTI MultiAtlas, SpineSeg and TBSS. After group comparisons, there was widespread microstructural damage in the cerebral white matter, including cerebellar peduncles, corpus callosum and pyramidal tracts of patients with FRDA. We also found gray matter volumetric reduction in the dentate nuclei of the cerebellum, brainstem and motor cortex. We did not find volumetric reduction over time, but there was progressive white matter microstructural damage in the corpus callosum, pyramidal tracts and superior cerebellar peduncles after 1 year of follow-up. Regarding the disease phenotypes, we found that both classical FRDA and LOFA have similar, but not identical neuroimaging signatures. Although subtle, the structural differences might help to explain the phenotypic differences seen in both conditions. The corticospinal tracts are damaged in both conditions, but more severely in the late-onset FRDA group, which may explain why pyramidal signs are more evident in the latter subgroup. We failed to identify iron deposits in brain regions other than the dentate nuclei of patients with FRDA. Finally, we found that the spinal cord and inferior cerebellar peduncles are the structures compromised in pediatric patients with FRDADoutoradoFisiopatologia MédicaDoutor em Ciências2014/19786-7, 2015/09793-9FAPES

Correlation between neurofunctional profile and sensory-motor skills of children with cerebral palsy

OBJECTIVE: to investigate the correlation between the profile neurofunctional and sensory motor skills of children with cerebral palsy. METHODS: the sample comprised 27 children with cerebral palsy. We used a neurological evaluation form to obtain the neurofunctional profile and Portage Inventory to evaluate sensorimotor development. RESULTS: the functional impairment is related to the greater degree of disability, change in tone and a deficit of body reactions of children. The body reactions correlate with each other and sensory changes. There was also a correlation between the five areas of development (motor, language, socialization, self-care and cognitive), indicating the importance of each to the overall performance of the human being. CONCLUSION: it was found that the deficit in the skills of these children is mainly related to the functional level, degree of disability, changes in the sensory system and flaws in bodily reactions. It is important to identify the correlation of these data in order to improve treatment and improve the physical functional performance of these children.OBJETIVO: verificar a correlação entre o perfil neurofuncional e as habilidades sensório-motoras de crianças com paralisia cerebral. MÉTODO: a amostra foi composta por 27 crianças com paralisia cerebral. Utilizou-se a ficha de avaliação neurológica para se obter os dados do perfil neurofuncional e o Inventário Portage Operacionalizado para avaliar o desenvolvimento sensório-motor. RESULTADOS: o comprometimento funcional está relacionado com o maior grau de incapacidade, alteração do tônus e déficit das reações corporais das crianças. As reações corporais correlacionam entre si e com as alterações sensoriais. Houve também correlação entre as cinco áreas do desenvolvimento (motora, de linguagem, socialização, autocuidado e cognitiva), indicando a importância de cada uma para o desempenho geral do ser humano. CONCLUSÃO: foi verificado que o déficit nas habilidades dessas crianças está relacionado principalmente ao nível funcional, grau de incapacidade, alterações no sistema sensorial e falhas nas reações corporais. É importante identificar a correlação desses dados a fim de aperfeiçoar o tratamento e melhorar o desempenho físico funcional dessas crianças

The Developing Human Connectome Project: a minimal processing pipeline for neonatal cortical surface reconstruction

The Developing Human Connectome Project (dHCP) seeks to create the first 4-dimensional connectome of early life. Understanding this connectome in detail may provide insights into normal as well as abnormal patterns of brain development. Following established best practices adopted by the WU-MINN Human Connectome Project (HCP), and pioneered by FreeSurfer, the project utilises cortical surface-based processing pipelines. In this paper, we propose a fully automated processing pipeline for the structural Magnetic Resonance Imaging (MRI) of the developing neonatal brain. This proposed pipeline consists of a refined framework for cortical and sub-cortical volume segmentation, cortical surface extraction, and cortical surface inflation, which has been specifically designed to address considerable differences between adult and neonatal brains, as imaged using MRI. Using the proposed pipeline our results demonstrate that images collected from 465 subjects ranging from 28 to 45 weeks post-menstrual age (PMA) can be processed fully automatically; generating cortical surface models that are topologically correct, and correspond well with manual evaluations of tissue boundaries in 85% of cases. Results improve on state-of-the-art neonatal tissue segmentation models and significant errors were found in only 2% of cases, where these corresponded to subjects with high motion. Downstream, these surfaces will enhance comparisons of functional and diffusion MRI datasets, supporting the modelling of emerging patterns of brain connectivity