Petra Hüppi
Université de Genève, Pediatrics, Faculty Member
Evidence exists that the developing organism adapts to the environment it finds itself. Short and long-term adjustments take place and will initially induce intrauterine growth retardation but will also have consequences that will appear... more
Evidence exists that the developing organism adapts to the environment it finds itself. Short and long-term adjustments take place and will initially induce intrauterine growth retardation but will also have consequences that will appear later in life. These adjustments are referred as "programming". The use of advanced magnetic resonance imaging techniques in IUGR babies has delineated changes in the development of the central nervous system that correlate with altered neurodevelopment and could be implicated in the development of neuropsychiatric disorders in adult life. In this review, we will delineate some modifications of CNS development and functions that occur after exposition to adverse environment and that can now be studied in vivo with advanced imaging technology.
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Research Interests: Diffusion Tensor Imaging, Medicine, Anisotropy, Corpus Callosum, Cerebral Cortex, and 15 moreMice, Animals, Motor Cortex, Brain Ischemia, Biotin, Clinical Sciences, Fractional Anisotropy, Age Factors, Neural pathways, Annals, Axons, DNA binding proteins, Mesenchymal Stromal Cells, Functional Laterality, and myelin basic protein
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Children born prematurely are at high risk for long-term abnormal development, including deficits in attentional abilities that persist throughout adolescence. The severity of these cognitive difficulties varies significantly among... more
Children born prematurely are at high risk for long-term abnormal development, including deficits in attentional abilities that persist throughout adolescence. The severity of these cognitive difficulties varies significantly among preterm-born children, with both the level of prematurity and sex being the most relevant factors for the determination of their neurodevelopmental outcomes. In order to understand the neurostructural correlate of these disabilities, we used a brain connectome approach to analyze the effects of gender and degree of prematurity on the attentional system network related to executive control in school age preterm children. Our results suggest that being born extremely premature, as well as being born male, differentially affects brain connectivity and development.
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Identification of neuroimaging biomarkers following extreme prematurity (EP) and intrauterine growth restriction (IUGR) is crucial for understanding their cognitive and behavioral impairments at school age
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Understanding rate and variability of connectivity in normal brain development can offer insight into the developmental origin of childhood and adult brain disorders. Indeed, there is increasing interest towards assessing the development... more
Understanding rate and variability of connectivity in normal brain development can offer insight into the developmental origin of childhood and adult brain disorders. Indeed, there is increasing interest towards assessing the development of white matter (WM) fibers underlying the complex brain connectivity [1], since the development of functional connections is clearly dependent on the establishment of cortical fiber pathways [2,3], their appropriate maturation and myelination. However, correlation of structural connectivity with specific brain cognitive and behavioral brain functioning can open the way to define quantitative and qualitative MRI biomarkers with the final scope of understanding brain organization and function. To goal of this work is to study the brain connectivity and network model based segregation of structural connectivity associated with cognitive and behavioral scores in prematurely born children. We used graph theory-based connectivity analysis and stepwise linear regression models to assess the contribution of brain connectivity as well as subjects co-variates as gestational age (GA) and birth weight (BW) in cognitive and behavioral performance of young children.
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Understanding mechanisms of injury and repair in the developing brain remains a challenge. Damage is the result of an acute injury and of subsequent modifications in brain development. The aim of the present study was to define the nature... more
Understanding mechanisms of injury and repair in the developing brain remains a challenge. Damage is the result of an acute injury and of subsequent modifications in brain development. The aim of the present study was to define the nature of acute and subsequent brain neurochemical profile alterations in a model of neonatal hypoxic-ischemic injury (HI) in the P3 rat pup using high-field MR imaging and spectroscopic techniques. P3 Wistar pups underwent moderate (HI) injury consisting of right carotid cauterization, and hypoxia for 30 minutes at 6% O 2 . 24 hours (P4, n = 8) and 8 days after HI (P11, n = 8) MRI and 1H-MRS was performed using a 9.4T magnet. 1H-MRS spectra within the ipsilateral and contralateral cortex were acquired. Injury was seen as an hyperintense signal in the ispilateral cortex. The volume of the brain in the HI group compared to the control was not significantly different at P4 but was reduced at P11. At P4 the neurochemical profile of the ipsilateral cortex indicated significant decreases of several metabolites (macromolecules, phosphocholine, creatine, inositol, N-acetyl aspartate, taurine, glutamate, glutamate/glutamine) reflecting an acute energetic and functional slowing-down in the injured cortex. At P11, only a few metabolites showed significant increase (phosphocreatine, glutamate, taurine, glutamate/glutamine). At P11, the variation of the metabolite concentrations need to be further investigated to define their role in this context. These results provide new in vivo insight into the neurochemical processes resulting from HI in the developing brain that can be used to monitor injury and the response to protective therapies.
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Intrauterine Growth Restriction (IUGR) due to placental insufficiency affects 5-10% of all pregnancies and it is associated with a wide range of short and long-term neurodevelopmental disorders. Different approaches have been considered... more
Intrauterine Growth Restriction (IUGR) due to placental insufficiency affects 5-10% of all pregnancies and it is associated with a wide range of short and long-term neurodevelopmental disorders. Different approaches have been considered to understand IUGR effects on brain development. Recently, connectomics has been used to analyze brain reorganization in IUGR children at one and six years of age. Connectomics estimates the brain network and describes it by different graph measures. Diffusion tensor imaging (DTI) can be used to infer the connectivity between regions, since it allows in-vivo estimation of fiber tracts inside the brain. In this study, DTI based connectomics was used to describe short- and long-term brain reorganization in IUGR. The connectome of a cohort of preterm IUGR and control children at 1, 6 and 9 years of age was estimated and analyzed to evaluate differences in the architecture of neural circuitry and its evolution during development.
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Fetal growth restriction (FGR) is principally caused by suboptimal placental function. Poor placental function causes an under supply of nutrients and oxygen to the developing fetus, restricting development of individual organs and... more
Fetal growth restriction (FGR) is principally caused by suboptimal placental function. Poor placental function causes an under supply of nutrients and oxygen to the developing fetus, restricting development of individual organs and overall growth. Estimated fetal weight below the 10th or 3rd percentile with uteroplacental dysfunction, and knowledge regarding the onset of growth restriction (early or late), provide diagnostic criteria for fetuses at greatest risk for adverse outcome. Brain development and function is altered with FGR, with ongoing clinical and preclinical studies elucidating neuropathological etiology. During the third trimester of pregnancy, from ~28 weeks gestation, neurogenesis is complete and neuronal complexity is expanding, through axonal and dendritic outgrowth, dendritic branching and synaptogenesis, accompanied by myelin production. Fetal compromise over this period, as occurs in FGR, has detrimental effects on these processes. Total brain volume and grey matter volume is reduced in infants with FGR, first evident in utero, with cortical volume particularly vulnerable. Imaging studies show that cerebral morphology is disturbed in FGR, with altered cerebral cortex, volume and organization of brain networks, and reduced connectivity of long- and short-range circuits. Thus, FGR induces a deviation in brain development trajectory affecting both grey and white matter, however grey matter volume is preferentially reduced, contributed by cell loss, and reduced neurite outgrowth of surviving neurons. In turn, cell-to-cell local networks are adversely affected in FGR, and whole brain left and right intrahemispheric connections and interhemispheric connections are altered. Importantly, disruptions to region-specific brain networks are linked to cognitive and behavioral impairments.
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Significance Preterm babies are cared for in neonatal intensive care units (NICU), which are busy places with a lot of mechanical noise increasingly recognized to disrupt normal brain development. NICUs therefore invest in developmental... more
Significance Preterm babies are cared for in neonatal intensive care units (NICU), which are busy places with a lot of mechanical noise increasingly recognized to disrupt normal brain development. NICUs therefore invest in developmental care procedures, with music for example, but neurobiological evidence for these interventions is missing. We present results from a clinical trial to study the effects of a music intervention on preterm infants’ brain development. Based on resting-state fMRI, we provide evidence that music enhanced connectivity in a brain circuitry involving the salience network with regions implicated in sensory and higher-order cognitive functions, previously found to be altered in preterm infants. To our knowledge, this study is unique in observing an impact of music on brain development in preterm newborns.
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The human brain is constantly evolving throughout lifetime, with some of the most spectacular changes taking place during the developmental period, which starts in utero and continues throughout adolescence. While the majority of the... more
The human brain is constantly evolving throughout lifetime, with some of the most spectacular changes taking place during the developmental period, which starts in utero and continues throughout adolescence. While the majority of the existing atlases address the adult brain, dedicated atlases are necessary to study the developing brain, which is fundamentally different from the adult brain in terms of structure, morphology, and tissue composition. In this article, we will address major challenges, existing solutions, and directions for future work in the construction of atlases for the developing brain, with a focus on digital atlases based on magnetic resonance imaging.
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Premature birth and the early exposure to environmental sensory information influence the cascade of histogenetic events that occur during the development of human telencephalon. The prenatal establishment of the genetically driven number... more
Premature birth and the early exposure to environmental sensory information influence the cascade of histogenetic events that occur during the development of human telencephalon. The prenatal establishment of the genetically driven number and size of the elements that constitute the neuronal architecture of the telencephalon (e.g. number of axonal fibres and neurons) is the basis for the lifelong neuronal reorganisation (e.g. synapse pruning, dendrite growth, axonal retraction and myelinisation). Our hypothesis was driven by the experimental data and data from literature according to which the results of early alteration of histogenetic prenatal events can be seen in childhood too. Thus, we have tested the effect of the premature birth and birth weight on the regional size of cerebral cortex (cortical thickness and cortical surface) at school age.
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Intrauterine Growth Restriction (IUGR) due to placental insufficiency affects 5-10% of all pregnancies and it is associated with a wide range of short and long-term neurodevelopmental disorders. Different approaches have been considered... more
Intrauterine Growth Restriction (IUGR) due to placental insufficiency affects 5-10% of all pregnancies and it is associated with a wide range of short and long-term neurodevelopmental disorders. Different approaches have been considered to understand IUGR effects on brain development. Recently, connectomics has been used to analyze brain reorganization in IUGR children at one and six years of age. Connectomics estimates the brain network and describes it by different graph measures. Diffusion tensor imaging (DTI) can be used to infer the connectivity between regions, since it allows in-vivo estimation of fiber tracts inside the brain. In this study, DTI based connectomics was used to describe short- and long-term brain reorganization in IUGR. The connectome of a cohort of preterm IUGR and control children at 1, 6 and 9 years of age was estimated and analyzed to evaluate differences in the architecture of neural circuitry and its evolution during development.
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Identification of neuroimaging biomarkers following extreme prematurity (EP) and intrauterine growth restriction (IUGR) is crucial for understanding their cognitive and behavioral impairments at school age
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years-old children Elda Fischi-Gomez, Emma Muñoz-Moreno, Lana Vasung, Djalel Eddine Meskaldji, Sebastien Urben, Maryline Monnier, Koviljka Barishnikov, Cristina Borradori-Tolsa, François Lazeyras, Jean-Philippe Thiran, and Petra Susan... more
years-old children Elda Fischi-Gomez, Emma Muñoz-Moreno, Lana Vasung, Djalel Eddine Meskaldji, Sebastien Urben, Maryline Monnier, Koviljka Barishnikov, Cristina Borradori-Tolsa, François Lazeyras, Jean-Philippe Thiran, and Petra Susan Hüppi Signal Processing Laboratory LTS5, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland, Division of Child Development and Growth. Department of Pediatrics, University of Geneva, Geneva, Switzerland, Fetal and Perinatal Medicine Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain, MIPLab, Institute of Bioengeneering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland, Department of Radiology and Medical Informatics, Faculty of Medicine, University of Geneva, Geneva, Switzerland, Child Clinical Neuropsychology Unit, Department of Psychology, University of Geneva, Geneva, Switzerland, Developmental Unit. Division of Neonatology (DMCP), University Hospital Center (CHUV), Lausanne, Switzerland, Department of Radiology, University Hospital Center (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
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Lactoferrin (Lf), component of maternal milk, has antioxidant, anti-inflammatory and antimicrobial properties. Neuroprotective effects of Lf on the immature brain have been recently shown in rodent models of intrauterine growth... more
Lactoferrin (Lf), component of maternal milk, has antioxidant, anti-inflammatory and antimicrobial properties. Neuroprotective effects of Lf on the immature brain have been recently shown in rodent models of intrauterine growth restriction and cerebral hypoxia/ischemia. Here we postulated that Lf could also have beneficial effects on preterm inflammatory brain injury. Lf was supplemented in maternal food during lactation and lipopolysaccharide (LPS) was injected in subcortical white matter of rat pups at postnatal day 3 (P3). Effect of maternal Lf supplementation was investigated 24 h (P4), 4 (P7), or 21 days (P24) after LPS injection mainly on the striatum. Lateral ventricle and brain structures volumes were quantified. Microstructure was evaluated by diffusion tensor imaging, neurite orientation dispersion and density imaging as well as electron microscopy. Neurochemical profile was measured by (1) H-magnetic resonance spectroscopy. GFAP protein, proinflammatory cytokines mRNA exp...
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Significant human brain growth occurs during the third trimester, with a doubling of whole brain volume and a fourfold increase of cortical gray matter volume. This is also the time period during which cortical folding and gyrification... more
Significant human brain growth occurs during the third trimester, with a doubling of whole brain volume and a fourfold increase of cortical gray matter volume. This is also the time period during which cortical folding and gyrification take place. Conditions such as intrauterine growth restriction, prematurity and cerebral white matter injury have been shown to affect brain growth including specific structures such as the hippocampus, with subsequent potentially permanent functional consequences. The use of 3D magnetic resonance imaging (MRI) and dedicated postprocessing tools to measure brain tissue volumes (cerebral cortical gray matter, white matter), surface and sulcation index can elucidate phenotypes associated with early behavior development. The use of diffusion tensor imaging can further help in assessing microstructural changes within the cerebral white matter and the establishment of brain connectivity. Finally, the use of functional MRI and resting-state functional MRI connectivity allows exploration of the impact of adverse conditions on functional brain connectivity in vivo. Results from studies using these methods have for the first time illustrated the structural impact of antenatal conditions and neonatal intensive care on the functional brain deficits observed after premature birth. In order to study the pathophysiology of these adverse conditions, MRI has also been used in conjunction with histology in animal models of injury in the immature brain. Understanding the histological substrate of brain injury seen on MRI provides new insights into the immature brain, mechanisms of injury and their imaging phenotype.
Research Interests: Neuroscience, Biomedical Engineering, Magnetic Resonance Imaging, Medicine, Diffusion MRI, and 15 moreAnatomy, Humans, Cerebral Cortex, Animals, Three Dimensional Imaging, Medical Physiology, Human Brain, Phenotype, Newborn Infant, White matter, Gyrification, Child behavior disorders, brain size, Nerve fibers, and Infant Premature
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Background. Advanced neuroimaging techniques have brought increasing recognition of cerebellar injury among premature infants. The developmental relationship between early brain injury and effects on the cerebrum and cerebellum remains... more
Background. Advanced neuroimaging techniques have brought increasing recognition of cerebellar injury among premature infants. The developmental relationship between early brain injury and effects on the cerebrum and cerebellum remains unclear. Objectives. To examine whether cerebral parenchymal brain lesions among preterm infants are associated with subsequent decreases in cerebellar volume and, conversely, whether primary cerebellar injury is associated with decreased cerebral brain volumes, with advanced, 3-dimensional, volumetric MRI at term gestational age equivalent. Methods. Total cerebellar volumes and cerebellar gray and myelinated white matter volumes were determined through manual outlining for 74 preterm infants with unilateral periventricular hemorrhagic infarction (14 infants), bilateral diffuse periventricular leukomalacia (20 infants), cerebellar hemorrhage (10 infants), or normal term gestational age equivalent MRI findings (30 infants). Total brain and right/left cerebral and cerebellar hemispheric volumes were calculated. Results. Unilateral cerebral brain injury was associated with significantly decreased volume of the contralateral cerebellar hemisphere. Conversely, unilateral primary cerebellar injury was associated with a contralateral decrease in supratentorial brain volume. Cerebellar gray matter and myelinated white matter volumes were reduced significantly not only among preterm infants with primary cerebellar hemorrhage but also among infants with cerebral parenchymal brain injury. Conclusions. These data suggest strongly that both reduction in contralateral cerebellar volume with unilateral cerebral parenchymal injury and reduction in total cerebellar volume with bilateral cerebral lesions are related to trophic transsynaptic effects. Early-life cerebellar injury may contribute importantly to the high rates of cognitive, behavioral, and motor deficits reported for premature infants.
Research Interests: Pediatrics, Magnetic Resonance Imaging, Medicine, Humans, Cerebellum, and 14 moreThree Dimensional Imaging, Brain injury, Newborn Infant, Dimensional, White matter, Trophic Interaction, Cerebral Hemorrhage, Cerebral Infarction, Psychology and Cognitive Sciences, Cerebrum, Premature infant, brain size, Medical and Health Sciences, and Infant Premature
Research Interests: Child Development, Diffusion Tensor Imaging, Electroencephalography, Infant Toddler Care, Brain development, and 15 moreBrain, Humans, Female, Electroencephalogram, Health Status, Intensive Care Unit, Fractional Anisotropy, Gestational Age, Brain Function, Infant Behavior, Experimental Group, Infant Care, Brain Structure and Function, Early experience, and Infant Premature
L’amelioration des soins perinataux a augmente le taux de survie des nouveau-nes prematures. L’environnement a un impact sur le developpement sensorimoteur et le comportement de l'enfant durant la periode neonatale. Le concept des... more
L’amelioration des soins perinataux a augmente le taux de survie des nouveau-nes prematures. L’environnement a un impact sur le developpement sensorimoteur et le comportement de l'enfant durant la periode neonatale. Le concept des soins de developpement est une approche multidisciplinaire et individualisee integrant les parents, premiers partenaires des soins. Cette prise en charge preventive soutient un developpement harmonieux de ces enfants vulnerables.
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Research Interests: Psychology, Computer Science, Magnetic Resonance Imaging, Medicine, Neuroimmunology, and 15 moreCephalometry, Brain, Humans, Cerebral Cortex, Female, Neuroimage, Male, Differential Diagnosis, Brain injury, Newborn Infant, Brain Structure, Indexation, Magnetic resonance image, Mesencephalon, and Medical and Health Sciences
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Preterm children born before 32 weeks of gestation represent 1% of the annual births in Switzerland, and are the most at risk of neurodevelopmental disabilities. A neurological surveillance is thus implemented in the neonatal units, and... more
Preterm children born before 32 weeks of gestation represent 1% of the annual births in Switzerland, and are the most at risk of neurodevelopmental disabilities. A neurological surveillance is thus implemented in the neonatal units, and multidisciplinary neurodevelopmental follow-up is offered to all our preterm patients. The follow-up clinics of the University hospitals in Lausanne and Geneva follow the Swiss guidelines for follow-up. An extended history and neurological examination is taken at each appointment, and a standardized test of development is performed. These examinations, which take place between the ages of 3 months and 9 years old, allow the early identification and treatment of developmental disorders frequent in this population, such as motor, cognitive or behavioral disorders, as well as the monitoring of the quality of neonatal care.
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Research Interests: Decision Making, Health Policy, Medicine, Clinical Ethics, Ethics and Decision-Making in Healthcare, and 13 moreHumans, End of life, Switzerland, Clinical Sciences, Newborn Infant, Intensive Care Unit, Neonatal Intensive Care Unit, Gestational Age, Guideline Adherence, Sedative, medical futility, Life support care, and withholding treatment
Neonatal Intensive Care Units (NICU) provide special equipment designed to give life support for the increasing number of prematurely born infants and assure their survival. More recently NICU's strive to include developmentally... more
Neonatal Intensive Care Units (NICU) provide special equipment designed to give life support for the increasing number of prematurely born infants and assure their survival. More recently NICU's strive to include developmentally oriented care and modulate sensory input for preterm infants. Music, among other sensory stimuli, has been introduced into NICUs, but without knowledge on the basic music processing in the brain of preterm infants. In this study, we explored the cortico-subcortical music processing of different types of conditions (Original music, Tempo modification, Key transposition) in newborns shortly after birth to assess the effective connectivity of the primary auditory cortex with the entire newborn brain. Additionally, we investigated if early exposure during NICU stay modulates brain processing of music in preterm infants at term equivalent age. We approached these two questions using Psychophysiological Interaction (PPI) analyses. A group of preterm infants li...