Ivica Kostovic

Croatian Institute for Brain Research · School of Medicine, University of Zagreb

Objective Congenital cytomegalovirus infection (cCMV) is a common, frequently unrecognized cause of childhood disability. The aim of the present study was to determine the symptoms that raise the suspicion of cCMV, define the neurodevelopmental outcomes, and assess their correlations. Methods This longitudinal observational study comprised 78 chil...

In humans, a quantifiable number of cortical synapses appears early in fetal life. In this paper, we present a bridge across different scales of resolution and the distribution of synapses across the transient cytoarchitectonic compartments: marginal zone (MZ), cortical plate (CP), subplate (SP), and in vivo MR images. The tissue of somatosensory c...

Objective To examine whether variation of regional cerebral oxygen saturation (rScO2) within three days after delivery predicts development of brain injury (intraventricular/cerebellar hemorrhage or white matter injury) in preterm infants. Study design A prospective study of neonates <32 weeks gestational age with normal cranial ultrasound admitte...

The intricate development of the human amygdala involves a complex interplay of diverse processes, varying in speed and duration. In humans, transient cytoarchitectural structures deliquesce, leading to the formation of functionally distinct nuclei as a result of multiple interdependent developmental events. This study compares the amygdala's cytoa...

Objectives To investigate the advantage of T1-weighted fast fluid-attenuated inversion-recovery MRI sequence without (T1-FFLAIR) and with compressed sensing technology (T1-FFLAIR-CS), which shows improved T1-weighted contrast, over standard used T1-weighted fast field echo (T1-FFE) sequence for the assessment of fetal myelination. Materials and me...

Abnormalities in neocortical and synaptic development are linked to neurodevelopmental disorders. However, the molecular and cellular mechanisms governing initial synapse formation in the prenatal neocortex remain poorly understood. Using polysome profiling coupled with snRNAseq on human cortical samples at various fetal phases, we identify human m...

Background: People with Down syndrome (DS) show clinical signs of accelerated ageing. Causative mechanisms remain unknown and hypotheses range from the (essentially untreatable) amplified-chromosomal-instability explanation, to potential actions of individual supernumerary chromosome-21 genes. The latter explanation could open a route to therapeut...

A link between maternal anxiety during pregnancy and adverse socio-emotional outcomes in childhood has been consistently sustained on the very early neurodevelopmental alteration of structural pathways between fetal limbic and cortical brain regions. In this study, we provide follow-up evidence for a feed-forward model linking (i) maternal anxiety,...

Human neurodevelopment is characterised by the appearance, development and disappearance or transformation of various transient structures that underlie the establishment of connectivity within and between future cortical and subcortical areas. Examples of transient structures in the forebrain (amongst many others) include the subpial granular laye...

Early regional patterning and laminar position of cortical projection neurons is determined by activation and deactivation of transcriptional factors (TFs) and RNA binding proteins (RBPs) that regulate spatiotemporal framework of neurogenetic processes (proliferation, migration, aggregation, postmigratory differentiation, molecular identity acquisi...

The cingulate gyrus, as a prominent part of the human limbic lobe, is involved in the integration and regulation of complex emotional, executive, motivational, and cognitive functions, attributed to several functional regions along the anteroposterior axis. In contrast to increasing knowledge of cingulate function in the adult brain, our knowledge...

Cerebral white matter undergoes a rapid and complex maturation during the early postnatal period. Prior magnetic resonance imaging (MRI) studies of early postnatal development have often been limited by small sample size, single-modality imaging, and univariate analytics. Here, we applied nonnegative matrix factorization, an unsupervised multivaria...

Microglia, the brain’s resident macrophages, shape neural development and are key neuroimmune hubs in the pathological signatures of neurodevelopmental disorders. Despite the importance of microglia, their development has not been carefully examined in the human brain, and most of our knowledge derives from rodents. We aimed to address this gap in...

Introduction: Maternal anxiety during pregnancy exerts detrimental effects on offspring neurodevelopment. At their core, these entail a dysregulation of the functional cross-talk between limbic structures and higher-order cognitive networks and a manifestation of behavioral profiles characterized by higher impulsivity and negative emotionality. To...

Little is known about the development of the human entorhinal cortex (EC), a major hub in a widespread network for learning and memory, spatial navigation, high‐order processing of object information, multimodal integration, attention and awareness, emotion, motivation, and perception of time. We analyzed a series of 20 fetal and two adult human br...

The neostriatum plays a central role in cortico-subcortical circuitry underlying goal-directed behavior. The adult mammalian neostriatum shows chemical and cytoarchitectonic compartmentalization in line with the connectivity. However, it is poorly understood how and when fetal compartmentalization (AChE-rich islands, nonreactive matrix) switches to...

During the early postnatal period, cerebral white matter undergoes rapid maturation through a complex series of interrelated cellular and histogenetic processes. Accurately quantifying these processes is important for improving understanding of early brain development, developmental abnormalities related to prematurity, and neurodevelopmental disea...

Low-risk premature infants often develop visual deficits, even in the absence of ophthalmological complications and high-graded brain injury. These complications can be explained by the nature of subtle perinatal lesions and alterations of brain growth due to prematurity. Subtle brain injuries and vulnerability of axonal pathways can be observed in...

White matter lesions in hypoxic-ischemic encephalopathy (HIE) are considered to be the important substrate of frequent neurological consequences in preterm infants. The aim of the study was to analyze volumes and tractographic parameters of the cortico-ponto-cerebellar axis to assess alterations in the periventricular fiber system and crossroads, c...

A population of more than six million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invas...

Abstract

Premature infants often develop visual deficits, including difficulties in tracking behavior, even in the absence of ophthalmological complications and high-graded brain injury. Finding neuroimaging markers, especially considering subtle lesions, would allow the appropriate follow-up and intervention inducing mechanisms of brain plasticity, promine...

Transient fetal zones are a characteristic feature of the developing human cerebral cortex. Neurons are born in the proliferative zones: ventricular (VZ) and subventricular zone (SVZ). Afterward, newly born neurons migrate through the intermediate zone (IZ) and subplate (SP) to reach their final destination, the cortical plate (CP). Development of...

Transient fetal zones are a characteristic feature of the developing human cerebral cortex. Proliferative ventricular (VZ) and subventricular (SVZ) zones are a major pool of neuroepithelial stem cells which are neural and glial precursors. After being born in proliferative zones, postmitotic neurons migrate through the intermediate (IZ) and subplat...

Microglia, the brain's resident macrophages, shape neural development and wiring, and are key neuroimmune hubs in the pathological signature of neurodevelopmental disorders. In the human brain, microglial development has not been carefully examined yet, and most of our knowledge derives from rodents. We established an unprecedented collection of 97...

Cytoarchitectonical parcellation of the visual cortex into the striate and extrastriate cortex requires complex histogenetic events within a precise spatio-temporal frame to attain the specification of areal domains and associated thalamocortical connections during the fetal brain development. We analyzed a deep subplate cellular monolayer (subplat...

During the second half of gestation, the human cerebrum undergoes pivotal histogenetic events that underlie functional connectivity. These include the growth, guidance, selection of axonal pathways, and their first engagement in neuronal networks. Here, we characterize the spatiotemporal patterns of cerebral connectivity in extremely preterm (EPT),...

INTRODUCTION: One of the most challenging pursuits in translational and clinical neuroscience is to find reliable criteria for prediction of neurological and cognitive outcome in prematurely born infants using available neuroimaging methods, such as magnetic resonance imaging (MRI). Previous studies showed that vulnerability of axonal pathways to h...

Disorders of consciousness (DOC) are one of the major consequences after anoxic or traumatic brain injury. So far, several studies have described the regaining of consciousness in DOC patients using deep brain stimulation (DBS). However, these studies often lack detailed data on the structural and functional cerebral changes after such treatment. T...

Cut-Like Homeobox 2 (Cux2) is a transcription factor involved in dendrite and spine development, and synapse formation of projection neurons placed in mouse upper neocortical layers. Therefore, Cux2 is often used as an upper layer marker in the mouse brain. However, expression of its orthologue CUX2 remains unexplored in the human fetal neocortex....

Sagittal strata represent bilateral, parasagittally oriented, white matter fiber system running from the frontal towards the occipital pole. They appear during the early fetal life, form trajectories of commissural, projection, and associative axonal pathways, and participate in the transformation of transient fetal zones/white matter segments into...

Histogenesis of human cerebral cortex and related subcortical structures begins at late embryonic period and finishes by adolescence. During this protracted period, various histogenetic events occur sequentially, but with partially overlapping manner, within defined cytoarchitectonical compartments, displaying growth spurts. Neurological developmen...

Aim: To explore the relationships between transient structural brain patterns on MRI at preterm and at term-equivalent age (TEA) as a predictor of general movements (GMs) and motor development at 1-year corrected age (CA) in very preterm infants. Methods: In this prospective study, 30 very preterm infants (median=28wks; 16 males) had structural ma...

Aim To explore the relationships between transient structural brain patterns on MRI at preterm and at term-equivalent age (TEA) as a predictor of general movements (GMs) and motor development at 1-year corrected age (CA) in very preterm infants. Methods In this prospective study, 30 very preterm infants (median = 28wks; 16 males) had structural ma...

The most prominent transient compartment of the primate fetal cortex is the deep, cell-sparse, synapse-containing subplate compartment (SPC). The developmental role of the SPC and its extraordinary size in humans remain enigmatic. This paper evaluates evidence on the development and connectivity of the SPC and discusses its role in the pathogenesis...

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders of genetic and environmental aetiologies. Some ASD cases are syndromic: associated with clinically defined patterns of somatic abnormalities and a neurobehavioural phenotype (e.g. Fragile X syndrome). Many cases, however, are idiopathic or non-syndromic. Such...

Neurodevelopment requires precise regulation of gene expression, including post-transcriptional regulatory events such as alternative splicing and mRNA translation. However, translational regulation of specific isoforms during neurodevelopment and the mechanisms behind it remain unknown. Using RNA-seq analysis of mouse neocortical polysomes, here w...

A population of >6 million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampl...

Objective: Brain volume reduction and association between altered volumes and neurodevelopmental outcomes have been reported in prematurely born children. As various cortical and subcortical regions play important role in motor development, local volume reductions might have implications for specific motor outcome. Our aim was to study the relation...

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The cerebral cortex constitutes more than half the volume of the human brain and is presumed to be responsible for the neuronal computations underlying complex phenomena, such as perception, thought, language, attention, episodic memory and voluntary movement. Rodent models are extremely valuable for the investigation of brain development, but cann...

Development of the cerebral wall is characterized by partially overlapping histogenetic events. However, little is known with regards to when, where, and how growing axonal pathways interact with progenitor cell lineages in the proliferative zones of the human fetal cerebrum. We analyzed the developmental continuity and spatial distribution of the...

The human brain develops slowly and over a long period of time which lasts for almost three decades. This enables good spatio-temporal resolution of histogenetic and neurogenetic events as well as an appropriate and clinically relevant timing of these events. In order to successfully apply in vivo neuroimaging data, in analyzing both the normal bra...

accepted for publication, in press

Magnetic resonance imaging (MRI) is an important tool in modern medicine, and functional magnetic resonance imaging (fMRI) is widely used for brain mapping and understanding cognitive behaviour in humans. As part of a larger study, 13 male candidates for Croatian military Special Forces (mean age + std = 25.77 + 3.27) were undertaken through a comp...

The cortex of primates is relatively expanded compared with many other mammals, yet little is known about what developmental processes account for the expansion of cortical subtype numbers in primates, including humans. We asked whether GABAergic and pyramidal neuron production occurs for longer than expected in primates than in mice in a sample of...

In this study, we aimed to identify major fiber pathways and their spatiotemporal relationships within transient fetal zones in the human fetal brain by comparing postmortem high-angular resolution diffusion MR imaging (HARDI) in combination with deterministic streamline tractography and histology. Diffusion weighted imaging was performed on postmo...

Example of the semi-automatic segmentation of the fetal brain during mid-fetal period. Fractional anisotropy (A,B) and dwi axial slices (C,D) used for segmentation of the cortical plate (red), proliferative zones (light blue), subplate zone (purple), intermediate zone (orange), thalamus (dark blue), corpus callosum (yellow), caudate nucleus (green)...

Thalamocortical (TH-C) fiber growth begins during the embryonic period and is completed by the third trimester of gestation in humans. Here we determined the timing and trajectories of somatosensory TH-C fibers in the developing human brain. We analyzed the periods of TH-C fiber outgrowth, path-finding, “waiting” in the subplate (SP), target select...

Significance The subplate zone, a transient cellular compartment of the embryonic cerebrum, has expanded in size and complexity during primate evolution, culminating in humans. Here, the application of multiple methods, including labeling time and place of neuronal origin and subsequent changes in their positions in macaque monkey embryos, and the...

The cerebral wall of the human fetal brain is composed of transient cellular compartments, which show characteristic spatiotemporal relationships with major neurogenic events (proliferation, migration, axonal growth, dendritic differentiation, synaptogenesis, cell death, and myelination). The aim of the present study was to obtain new quantitative...

This article describes sequential reorganization of transient cellular compartments of the fetal cerebral wall as spatial framework for dynamic enfolding of complex cellular histogenetic events (neuronal proliferation and migration, axon growth and synaptogenesis, specification of neuronal phenotypes, etc.), leading to the establishment of human co...

In the human brain, the development of structural connectivity starts during the early fetal period and progresses in a complex but sequential way, until all major axonal pathways become established in the preterm period, as outlined by postmortem and in vivo studies based on histological stainings and MRI. Through the myelination process, these ne...

The neural extracellular matrix (ECM) provides a supportive framework for differentiating cells and their processes and regulates morphogenetic events by spatially and temporally relevant localization of signaling molecules and by direct signaling via receptor and/or coreceptor-mediated action. The embryonic human brain and fetal human brain contai...

The Zagreb Collection of developing and adult human brains consists of approximately 1,300 brains of fetuses, children and adults that were collected following routine autopsies in the period from 1974 to 2014. The collection comprises brains of different normal developmental stages that may serve for investigation of normal human brain development...

The human fetal cerebral cortex develops through a series of partially overlapping histogenetic events which occur in transient cellular compartments, such as the subplate zone. The subplate serves as waiting compartment for cortical afferent fibers, the major site of early synaptogenesis and neuronal differentiation and the hub of the transient fe...