Publications by authors named "Lana Vasung"

43 Publications

Process of cortical network formation and impact of early brain damage.

Curr Opin Neurol 2014 Apr;27(2):133-41

aDepartment of Neurosciences, University of Geneva Medical School bChild Development Unit, Department of Pediatrics, School of Medicine, University of Geneva, Geneva, Switzerland.

Purpose Of Review: The aim is to review mechanisms that are central to the formation of proper cortical circuitry and relevant to perinatal brain injury and premature birth.

Recent Findings: Clinical investigations using noninvasive imaging techniques suggest that impaired connectivity of cortical circuitry is associated with perinatal adverse conditions. Recent experimental and translational studies revealed developmental mechanisms that are critical for circuit formation and potentially at risk in the perinatal period. These include existence of last wave genesis, migration and integration of gamma-aminobutyric acid (GABA) interneurons in the perinatal period; maturation of GABA interneuron networks that are central to critical period plasticity; transient connections by subplate neurons that guide thalamocortical connectivity, and a perineuronal microglia network that maintains axonal growth and neuronal survival as well as executing synaptic pruning. In addition, recent work has demonstrated that birth plays a key role in triggering the maturation cascade of cortical circuits.

Summary: Altered maturation of cortical circuits is an increasingly recognized aspect of perinatal injury and premature birth. Potential mechanisms are revealed but further translational studies are required to associate fine changes at the cellular and molecular level with imaging data in experimental models.
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http://dx.doi.org/10.1097/WCO.0000000000000068DOI Listing
April 2014

MRI of animal models of developmental disorders and translation to human imaging.

Curr Opin Neurol 2014 Apr;27(2):157-67

aDivision of Child Development and Growth, Department of Pediatrics, University of Geneva, Geneva bLaboratory of Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

Purpose Of Review: In order to understand the pathophysiological mechanisms leading to the specific brain alterations observed in immature newborn babies, preclinical studies on animal models mimicking clinical reality are mandatory and are ideally coupled with imaging modalities transferable to the human scenario. The availability of MRI techniques on both clinical and animal scanners allows this methodological transfer from bench to bedside. The aim of this review is to give an overview of the recent findings in MRI of animal models of developmental disorders and emphasize what we can learn from MRI on these models.

Recent Findings: Progress in newborn medicine has allowed the survival of increasingly immature newborns that is often associated with specific morbidities. The brain in particular shows developmentally linked vulnerability leading to specific brain injury and subsequent developmental disorders. MRI delivers a large amount of anatomical, microstructural and functional information and has been widely used to monitor cerebral development and characterize the specificity of brain lesions in the immature brain in humans and animal models.

Summary: In this review, we will present the different animal models assessed by magnetic resonance techniques and the histopathological correlations observed, as well as the implications for human imaging.
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http://dx.doi.org/10.1097/WCO.0000000000000066DOI Listing
April 2014

The role of neuroimaging in predicting neurodevelopmental outcomes of preterm neonates.

Clin Perinatol 2014 Mar 12;41(1):257-83. Epub 2013 Dec 12.

The Division of Development and Growth, Department of Paediatrics, Children's Hospital Geneva, 6 rue Willy Donzé, 1211 Geneva, Switzerland. Electronic address:

Magnetic resonance imaging (MRI) is a safe and high-resolution neuroimaging modality that is increasingly used in the neonatal population to assess brain injury and its consequences on brain development. It is superior to cranial ultrasound for the definition of patterns of both white and gray matter maturation and injury and therefore has the potential to provide prognostic information on the neurodevelopmental outcomes of the preterm population. Furthermore, the development of sophisticated MRI strategies, including diffusion tensor imaging, resting state functional connectivity, and magnetic resonance spectroscopy, may increase the prognostic value, helping to guide parental counseling and allocate early intervention services.
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http://dx.doi.org/10.1016/j.clp.2013.10.003DOI Listing
March 2014

Gaining insight of fetal brain development with diffusion MRI and histology.

Int J Dev Neurosci 2014 Feb 21;32:11-22. Epub 2013 Jun 21.

Croatian Institute for Brain Research, University of Zagreb, Croatia.

Human brain is extraordinarily complex and yet its origin is a simple tubular structure. Its development during the fetal period is characterized by a series of accurately organized events which underlie the mechanisms of dramatic structural changes during fetal development. Revealing detailed anatomy at different stages of human fetal brain development provides insight on understanding not only this highly ordered process, but also the neurobiological foundations of cognitive brain disorders such as mental retardation, autism, schizophrenia, bipolar and language impairment. Diffusion tensor imaging (DTI) and histology are complementary tools which are capable of delineating the fetal brain structures at both macroscopic and microscopic levels. In this review, the structural development of the fetal brains has been characterized with DTI and histology. Major components of the fetal brain, including cortical plate, fetal white matter and cerebral wall layer between the ventricle and subplate, have been delineated with DTI and histology. Anisotropic metrics derived from DTI were used to quantify the microstructural changes during the dynamic process of human fetal cortical development and prenatal development of other animal models. Fetal white matter pathways have been traced with DTI-based tractography to reveal growth patterns of individual white matter tracts and corticocortical connectivity. These detailed anatomical accounts of the structural changes during fetal period may provide the clues of detecting developmental and cognitive brain disorders at their early stages. The anatomical information from DTI and histology may also provide reference standards for diagnostic radiology of premature newborns.
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http://dx.doi.org/10.1016/j.ijdevneu.2013.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3825830PMC
February 2014

Region-specific reduction in brain volume in young adults with perinatal hypoxic-ischaemic encephalopathy.

Eur J Paediatr Neurol 2013 Nov 6;17(6):608-14. Epub 2013 Jun 6.

Department of Paediatric Neurology, University Children's Hospital, University Medical Centre Ljubljana, Bohoriceva 20, 1000 Ljubljana, Slovenia. Electronic address:

Background: A severe form of perinatal hypoxic-ischaemic encephalopathy (HIE) carries a high risk of perinatal death and severe neurological sequelae while in mild HIE only discrete cognitive disorders may occur.

Aim: To compare total brain volumes and region-specific cortical measurements between young adults with mild-moderate perinatal HIE and a healthy control group of the same age.

Methods: MR imaging was performed in a cohort of 14 young adults (9 males, 5 females) with a history of mild or moderate perinatal HIE. The control group consisted of healthy participants, matched with HIE group by age and gender. Volumetric analysis was done after the processing of MR images using a fully automated CIVET pipeline. We measured gyrification indexes, total brain volume, volume of grey and white matter, and of cerebrospinal fluid. We also measured volume, thickness and area of the cerebral cortex in the parietal, occipital, frontal, and temporal lobe, and of the isthmus cinguli, parahippocampal and cingulated gyrus, and insula.

Results: The HIE patient group showed smaller absolute volumetric data. Statistically significant (p < 0.05) reductions of gyrification index in the right hemisphere, of cortical areas in the right temporal lobe and parahippocampal gyrus, of cortical volumes in the right temporal lobe and of cortical thickness in the right isthmus of the cingulate gyrus were found. Comparison between the healthy group and the HIE group of the same gender showed statistically significant changes in the male HIE patients, where a significant reduction was found in whole brain volume; left parietal, bilateral temporal, and right parahippocampal gyrus cortical areas; and bilateral temporal lobe cortical volume.

Conclusions: Our analysis of total brain volumes and region-specific corticometric parameters suggests that mild-moderate forms of perinatal HIE lead to reductions in whole brain volumes. In the study reductions were most pronounced in temporal lobe and parahippocampal gyrus.
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http://dx.doi.org/10.1016/j.ejpn.2013.05.005DOI Listing
November 2013

Multimodality evaluation of the pediatric brain: DTI and its competitors.

Pediatr Radiol 2013 Jan 4;43(1):60-8. Epub 2013 Jan 4.

Division of Development and Growth, Department of Pediatrics, University of Geneva, University Hospital Geneva, Rue Willy-Donzé 6, 1211 Genève 14, Geneva, Switzerland.

The development of the human brain, from the fetal period until childhood, happens in a series of intertwined neurogenetical and histogenetical events that are influenced by environment. Neuronal proliferation and migration, cell aggregation, axonal ingrowth and outgrowth, dendritic arborisation, synaptic pruning and myelinisation contribute to the 'plasticity of the developing brain'. These events taken together contribute to the establishment of adult-like neuroarchitecture required for normal brain function. With the advances in technology today, mostly due to the development of non-invasive neuroimaging tools, it is possible to analyze these structural events not only in anatomical space but also longitudinally in time. In this review we have highlighted current 'state of the art' neuroimaging tools. Development of the new MRI acquisition sequences (DTI, CHARMED and phase imaging) provides valuable insight into the changes of the microstructural environment of the cortex and white matter. Development of MRI imaging tools dedicated for analysis of the acquired images (i) TBSS and ROI fiber tractography, (ii) new tissue segmentation techniques and (iii) morphometric analysis of the cortical mantle (cortical thickness and convolutions) allows the researchers to map the longitudinal changes in the macrostructure of the developing brain that go hand-in-hand with the acquisition of cognitive skills during childhood. Finally, the latest and the newest technologies, like connectom analysis and resting state fMRI connectivity analysis, today, for the first time provide the opportunity to study the developing brain through the prism of maturation of the systems and networks beyond individual anatomical areas. Combining these methods in the future and modeling the hierarchical organization of the brain might ultimately help to understand the mechanisms underlying complex brain structure function relationships of normal development and of developmental disorders.
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http://dx.doi.org/10.1007/s00247-012-2515-yDOI Listing
January 2013

Perinatal and early postnatal reorganization of the subplate and related cellular compartments in the human cerebral wall as revealed by histological and MRI approaches.

Brain Struct Funct 2014 Jan 19;219(1):231-53. Epub 2012 Dec 19.

Croatian Institute for Brain Research, University of Zagreb School of Medicine, Šalata 12, 10000, Zagreb, Croatia,

We analyzed the developmental history of the subplate and related cellular compartments of the prenatal and early postnatal human cerebrum by combining postmortem histological analysis with in vivo MRI. Histological analysis was performed on 21 postmortem brains (age range: 26 postconceptional weeks to 6.5 years) using Nissl staining, AChE-histochemistry, PAS-Alcian blue histochemistry, Gallyas' silver impregnation, and immunocytochemistry for MAP2, synaptophysin, neurofilament, chondroitin sulfate, fibronectin, and myelin basic protein. The histological findings were correlated with in vivo MRI findings obtained in 30 age-matched fetuses, infants, and children. We analyzed developmental reorganization of major cellular (cell bodies, growing axons) and extracellular (extracellular matrix) components of the subplate and the developing cortex/white matter interface. We found that perinatal and postnatal reorganization of these tissue components is protracted (extending into the second year of life) and characterized by well-delineated, transient and previously undescribed structural and molecular changes at the cortex/white matter interface. The findings of this study are clinically relevant because they may inform and guide a proper interpretation of highly dynamic and hitherto puzzling changes of cortical thickness and cortical/white matter interface as described in current in vivo MRI studies.
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http://dx.doi.org/10.1007/s00429-012-0496-0DOI Listing
January 2014

Coupling diffusion imaging with histological and gene expression analysis to examine the dynamics of cortical areas across the fetal period of human brain development.

Cereb Cortex 2013 Nov 28;23(11):2620-31. Epub 2012 Aug 28.

Advanced Imaging Research Center.

As a prominent component of the human fetal brain, the structure of the cerebral wall is characterized by its laminar organization which includes the radial glial scaffold during fetal development. Diffusion tensor imaging (DTI) is useful to quantitatively delineate the microstructure of the developing brain and to clearly identify transient fetal layers in the cerebral wall. In our study, the spatio-temporal microstructural changes in the developing human fetal cerebral wall were quantitatively characterized with high-resolution DTI data of postmortem fetal brains from 13 to 21 gestational weeks. Eleven regions of interest for each layer in the entire cerebral wall were included. Distinctive time courses of microstructural changes were revealed for 11 regions of the neocortical plate. A histological analysis was also integrated to elucidate the relationship between DTI fractional anisotropy (FA) and histology. High FA values correlated with organized radial architecture in histological image. Expression levels of 17565 genes were quantified for each of 11 regions of human fetal neocortex from 13 to 21 gestational weeks to identify transcripts showing significant correlation with FA change. These correlations suggest that the heterogeneous and regionally specific microstructural changes of the human neocortex are related to different gene expression patterns.
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http://dx.doi.org/10.1093/cercor/bhs241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792738PMC
November 2013

Species-dependent posttranscriptional regulation of NOS1 by FMRP in the developing cerebral cortex.

Cell 2012 May;149(4):899-911

Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.

Fragile X syndrome (FXS), the leading monogenic cause of intellectual disability and autism, results from loss of function of the RNA-binding protein FMRP. Here, we show that FMRP regulates translation of neuronal nitric oxide synthase 1 (NOS1) in the developing human neocortex. Whereas NOS1 mRNA is widely expressed, NOS1 protein is transiently coexpressed with FMRP during early synaptogenesis in layer- and region-specific pyramidal neurons. These include midfetal layer 5 subcortically projecting neurons arranged into alternating columns in the prospective Broca's area and orofacial motor cortex. Human NOS1 translation is activated by FMRP via interactions with coding region binding motifs absent from mouse Nos1 mRNA, which is expressed in mouse pyramidal neurons, but not efficiently translated. Correspondingly, neocortical NOS1 protein levels are severely reduced in developing human FXS cases, but not FMRP-deficient mice. Thus, alterations in FMRP posttranscriptional regulation of NOS1 in developing neocortical circuits may contribute to cognitive dysfunction in FXS.
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http://dx.doi.org/10.1016/j.cell.2012.02.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351852PMC
May 2012

The Zagreb Collection of human brains: a unique, versatile, but underexploited resource for the neuroscience community.

Ann N Y Acad Sci 2011 May;1225 Suppl 1:E105-30

University of Zagreb School of Medicine, Croatian Institute for Brain Research, Zagreb, Croatia.

The Zagreb Collection of developing and adult human brains was founded in 1974 by Ivica Kostović and consists of 1,278 developing and adult human brains, including 610 fetal, 317 children, and 359 adult brains. It is one of the largest collections of developing human brains. The collection serves as a key resource for many focused research projects and has led to several seminal contributions on mammalian cortical development, such as the discovery of the transient fetal subplate zone and of early bilaminar synaptogenesis in the embryonic and fetal human cerebral cortex, and the first description of growing afferent pathways in the human fetal telencephalon. The Zagreb Collection also serves as a core resource for ever-growing networks of international collaboration and represents the starting point for many young investigators who now pursue independent research careers at leading international institutions. The Zagreb Collection, however, remains underexploited owing to a lack of adequate funding in Croatia. Funding could establish an online catalog of the collection and modern virtual microscopy scanning methods to make the collection internationally more accessible.
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http://dx.doi.org/10.1111/j.1749-6632.2011.05993.xDOI Listing
May 2011

Neuroimaging of cortical development and brain connectivity in human newborns and animal models.

J Anat 2010 Oct;217(4):418-28

NICU, Department of Pediatrics, University of Geneva, Geneva, Switzerland.

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.
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http://dx.doi.org/10.1111/j.1469-7580.2010.01280.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992417PMC
October 2010

Development of axonal pathways in the human fetal fronto-limbic brain: histochemical characterization and diffusion tensor imaging.

J Anat 2010 Oct;217(4):400-17

Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 12, Zagreb, Croatia.

The development of cortical axonal pathways in the human brain begins during the transition between the embryonic and fetal period, happens in a series of sequential events, and leads to the establishment of major long trajectories by the neonatal period. We have correlated histochemical markers (acetylcholinesterase (AChE) histochemistry, antibody against synaptic protein SNAP-25 (SNAP-25-immunoreactivity) and neurofilament 200) with the diffusion tensor imaging (DTI) database in order to make a reconstruction of the origin, growth pattern and termination of the pathways in the period between 8 and 34 postconceptual weeks (PCW). Histological sections revealed that the initial outgrowth and formation of joined trajectories of subcortico-frontal pathways (external capsule, cerebral stalk-internal capsule) and limbic bundles (fornix, stria terminalis, amygdaloid radiation) occur by 10 PCW. As early as 11 PCW, major afferent fibers invade the corticostriatal junction. At 13-14 PCW, axonal pathways from the thalamus and basal forebrain approach the deep moiety of the cortical plate, causing the first lamination. The period between 15 and 18 PCW is dominated by elaboration of the periventricular crossroads, sagittal strata and spread of fibers in the subplate and marginal zone. Tracing of fibers in the subplate with DTI is unsuccessful due to the isotropy of this zone. Penetration of the cortical plate occurs after 24-26 PCW. In conclusion, frontal axonal pathways form the periventricular crossroads, sagittal strata and 'waiting' compartments during the path-finding and penetration of the cortical plate. Histochemistry is advantageous in the demonstration of a growth pattern, whereas DTI is unique for demonstrating axonal trajectories. The complexity of fibers is the biological substrate of selective vulnerability of the fetal white matter.
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http://dx.doi.org/10.1111/j.1469-7580.2010.01260.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2992416PMC
October 2010

Insights from in vitro fetal magnetic resonance imaging of cerebral development.

Semin Perinatol 2009 Aug;33(4):220-33

Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.

The development of the cerebral cortex, white matter microstructure, and the basal ganglia can be well characterized using structural magnetic resonance imaging (MRI). In this review, we analyzed structural in vitro MRI studies of transient cellular cerebral zones that are sites of neurogenetic events (proliferation, migration, cell aggregation, growth of axonal pathways, myelinization, and synaptogenesis). During early fetal life, from 9-13 postconceptional weeks, a thick, densely packed cellular ventricular/subventricular zone and ganglionic eminence indicate intensive proliferation of neuroepithelial stem cells. During the mid and late fetal phase, other cellular zones also became discernable: (1) the intermediate zone as a migratory and axonal growth zone; (2) the subplate zone as a synaptic, extracellular matrix-rich "waiting" compartment; and (3) the cell-dense cortical plate with postmigratory neurons. The preterm phase is characterized by the growth of cortical, thalamic, and striatal pathways; formation of white matter segments; and stratification within the subplate. Thalamocortical fibers cause lamination in the cortical plate, which leads to the formation of a substrate of sensory input. Preterm cerebral immaturity is characterized by considerable extracellular space at sites of axonal growth and a delineable subplate. The intensity of axonal growth, together with a high, gradient-dependent requirement for axonal guidance, forms a substrate for selective vulnerability of specific segments of cerebral white matter in the preterm brain. In summary, the combination of in vitro MRI, histologic analysis, and in vivo MRI is a promising new approach for studying the etiology and treatment of developmental disorders.
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http://dx.doi.org/10.1053/j.semperi.2009.04.003DOI Listing
August 2009