Publications by authors named "Ivica Kostovic"

55 Publications

Structural changes in brains of patients with disorders of consciousness treated with deep brain stimulation.

Sci Rep 2021 Feb 23;11(1):4401. Epub 2021 Feb 23.

Department of Neurosurgery, Dubrava University Hospital, Avenija Gojka Suska 6, 10000, Zagreb, Croatia.

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. The aim of this study was to conduct a volumetric analysis of specific cortical and subcortical structures to determine the impact of DBS after functional recovery of DOC patients. Five DOC patients underwent unilateral DBS electrode implantation into the centromedian parafascicular complex of the thalamic intralaminar nuclei. Consciousness recovery was confirmed using the Rappaport Disability Rating and the Coma/Near Coma scale. Brain MRI volumetric measurements were done prior to the procedure, then approximately a year after, and finally 7 years after the implementation of the electrode. The volumetric analysis included changes in regional cortical volumes and thickness, as well as in subcortical structures. Limbic cortices (parahippocampal and cingulate gyrus) and paralimbic cortices (insula) regions showed a significant volume increase and presented a trend of regional cortical thickness increase 1 and 7 years after DBS. The volumes of related subcortical structures, namely the caudate, the hippocampus as well as the amygdala, were significantly increased 1 and 7 years after DBS, while the putamen and nucleus accumbens presented with volume increase. Volume increase after DBS could be a result of direct DBS effects, or a result of functional recovery. Our findings are in accordance with the results of very few human studies connecting DBS and brain volume increase. Which mechanisms are behind the observed brain changes and whether structural changes are caused by consciousness recovery or DBS in patients with DOC is still a matter of debate.
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http://dx.doi.org/10.1038/s41598-021-83873-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902623PMC
February 2021

Transient structural MRI patterns correlate with the motor functions in preterm infants.

Brain Dev 2021 Mar 22;43(3):363-371. Epub 2020 Nov 22.

Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience, Croatian Institute for Brain Research, University of Zagreb, School of Medicine, Croatia.

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 magnetic resonance imaging (MRI) at preterm (median = 31wks + 6d) and at TEA (median = 40wks) and neuromotor assessments. The quality of GMs was assessed by Prechtl's general movements assessment and a detailed analysis of the motor repertoire was performed by calculating a motor optimality score (MOS), both at term age and at 3 months post-term. Motor development at 1-year CA was evaluated with the Infant Motor Profile (IMP). Associations between qualitative MRI findings and neuromotor scores were investigated.

Results: Abnormal GMs and low motor performance at 1-year CA were associated with the poor visibility of transient structural pattern, that is with sagittal strata.

Interpretation: Transient structural MRI pattern, sagittal strata, at preterm age is related to the quality of GMs and later motor development in preterm infants. This transient fetal brain compartment may be considered as a component of neurobiological basis for early neuromotor behavior, as expressed by GMs.
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http://dx.doi.org/10.1016/j.braindev.2020.11.002DOI Listing
March 2021

The enigmatic fetal subplate compartment forms an early tangential cortical nexus and provides the framework for construction of cortical connectivity.

Authors:
Ivica Kostović

Prog Neurobiol 2020 11 11;194:101883. Epub 2020 Jul 11.

Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience, Salata 12, 10000 Zagreb, Croatia. Electronic address:

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 of neurodevelopmental disorders. A synthesis of data shows that the subplate becomes a prominent compartment by its expansion from the deep cortical plate (CP), appearing well-delineated on MR scans and forming a tangential nexus across the hemisphere, consisting of an extracellular matrix, randomly distributed postmigratory neurons, multiple branches of thalamic and long corticocortical axons. The SPC generates early spontaneous non-synaptic and synaptic activity and mediates cortical response upon thalamic stimulation. The subplate nexus provides large-scale interareal connectivity possibly underlying fMR resting-state activity, before corticocortical pathways are established. In late fetal phase, when synapses appear within the CP, transient the SPC coexists with permanent circuitry. The histogenetic role of the SPC is to provide interactive milieu and capacity for guidance, sorting, "waiting" and target selection of thalamocortical and corticocortical pathways. The new evolutionary role of the SPC and its remnant white matter neurons is linked to the increasing number of associative pathways in the human neocortex. These roles attributed to the SPC are regulated using a spatiotemporal gene expression during critical periods, when pathogenic factors may disturb vulnerable circuitry of the SPC, causing neurodevelopmental cognitive circuitry disorders.
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http://dx.doi.org/10.1016/j.pneurobio.2020.101883DOI Listing
November 2020

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.

Mol Psychiatry 2020 Jul 10. Epub 2020 Jul 10.

Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Singapore.

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-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21 organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (Aβ1-20 and Aβ1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.
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http://dx.doi.org/10.1038/s41380-020-0806-5DOI Listing
July 2020

Autism Spectrum Disorders: Multiple Routes to, and Multiple Consequences of, Abnormal Synaptic Function and Connectivity.

Neuroscientist 2021 02 22;27(1):10-29. Epub 2020 May 22.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, Oxfordshire, UK.

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders of genetic and environmental etiologies. Some ASD cases are syndromic: associated with clinically defined patterns of somatic abnormalities and a neurobehavioral phenotype (e.g., Fragile X syndrome). Many cases, however, are idiopathic or non-syndromic. Such disorders present themselves during the early postnatal period when language, speech, and personality start to develop. ASDs manifest by deficits in social communication and interaction, restricted and repetitive patterns of behavior across multiple contexts, sensory abnormalities across multiple modalities and comorbidities, such as epilepsy among many others. ASDs are disorders of connectivity, as synaptic dysfunction is common to both syndromic and idiopathic forms. While multiple theories have been proposed, particularly in idiopathic ASDs, none address why certain brain areas (e.g., frontotemporal) appear more vulnerable than others or identify factors that may affect phenotypic specificity. In this hypothesis article, we identify possible routes leading to, and the consequences of, altered connectivity and review the evidence of central and peripheral synaptic dysfunction in ASDs. We postulate that phenotypic specificity could arise from aberrant experience-dependent plasticity mechanisms in frontal brain areas and peripheral sensory networks and propose why the vulnerability of these areas could be part of a model to unify preexisting pathophysiological theories.
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http://dx.doi.org/10.1177/1073858420921378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804368PMC
February 2021

Translational derepression of Elavl4 isoforms at their alternative 5' UTRs determines neuronal development.

Nat Commun 2020 04 3;11(1):1674. Epub 2020 Apr 3.

Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA.

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 we report translationally repressed and derepressed mRNA isoforms during neocortical neurogenesis whose orthologs include risk genes for neurodevelopmental disorders. We demonstrate that the translation of distinct mRNA isoforms of the RNA binding protein (RBP), Elavl4, in radial glia progenitors and early neurons depends on its alternative 5' UTRs. Furthermore, 5' UTR-driven Elavl4 isoform-specific translation depends on upstream control by another RBP, Celf1. Celf1 regulation of Elavl4 translation dictates development of glutamatergic neurons. Our findings reveal a dynamic interplay between distinct RBPs and alternative 5' UTRs in neuronal development and underscore the risk of post-transcriptional dysregulation in co-occurring neurodevelopmental disorders.
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http://dx.doi.org/10.1038/s41467-020-15412-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125149PMC
April 2020

New insights into the development of the human cerebral cortex.

J Anat 2019 09 2;235(3):432-451. Epub 2019 Aug 2.

Department of Neurology, University of California, San Francisco (UCSF), San Francisco, CA, USA.

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 cannot provide insight into aspects that are unique or highly derived in humans. Many human psychiatric and neurological conditions have developmental origins but cannot be studied adequately in animal models. The human cerebral cortex has some unique genetic, molecular, cellular and anatomical features, which need to be further explored. The Anatomical Society devoted its summer meeting to the topic of Human Brain Development in June 2018 to tackle these important issues. The meeting was organized by Gavin Clowry (Newcastle University) and Zoltán Molnár (University of Oxford), and held at St John's College, Oxford. The participants provided a broad overview of the structure of the human brain in the context of scaling relationships across the brains of mammals, conserved principles and recent changes in the human lineage. Speakers considered how neuronal progenitors diversified in human to generate an increasing variety of cortical neurons. The formation of the earliest cortical circuits of the earliest generated neurons in the subplate was discussed together with their involvement in neurodevelopmental pathologies. Gene expression networks and susceptibility genes associated to neurodevelopmental diseases were discussed and compared with the networks that can be identified in organoids developed from induced pluripotent stem cells that recapitulate some aspects of in vivo development. New views were discussed on the specification of glutamatergic pyramidal and γ-aminobutyric acid (GABA)ergic interneurons. With the advancement of various in vivo imaging methods, the histopathological observations can be now linked to in vivo normal conditions and to various diseases. Our review gives a general evaluation of the exciting new developments in these areas. The human cortex has a much enlarged association cortex with greater interconnectivity of cortical areas with each other and with an expanded thalamus. The human cortex has relative enlargement of the upper layers, enhanced diversity and function of inhibitory interneurons and a highly expanded transient subplate layer during development. Here we highlight recent studies that address how these differences emerge during development focusing on diverse facets of our evolution.
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http://dx.doi.org/10.1111/joa.13055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704245PMC
September 2019

The Zagreb Collection of human brains: entering the virtual world.

Croat Med J 2018 Dec;59(6):283-287

Pero Hrabač, Department of Medical Statistics, Epidemiology, and Medical Informatics, "Andrija Štampar" School of Public Health, University of Zagreb School of Medicine, Zagreb, Croatia,

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330769PMC
December 2018

Sublaminar organization of the human subplate: developmental changes in the distribution of neurons, glia, growing axons and extracellular matrix.

J Anat 2019 09 13;235(3):481-506. Epub 2018 Dec 13.

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

The objective of this paper was to collect normative data essential for analyzing the subplate (SP) role in pathogenesis of developmental disorders, characterized by abnormal circuitry, such as hypoxic-ischemic lesions, autism and schizophrenia. The main cytological features of the SP, such as low cell density, early differentiation of neurons and glia, plexiform arrangement of axons and dendrites, presence of synapses and a large amount of extracellular matrix (ECM) distinguish this compartment from the cell-dense cortical plate (CP; towards pia) and large fiber bundles of external axonal strata of fetal white matter (towards ventricle). For SP delineation from these adjacent layers based on combined cytological criteria, we analyzed the sublaminar distribution of different microstructural elements and the associated maturational gradients throughout development, using immunocytochemical and histological techniques on postmortem brain material (Zagreb Neuroembryological Collection). The analysis revealed that the SP compartment of the lateral neocortex shows changes in laminar organization throughout fetal development: the monolayer in the early fetal period (presubplate) undergoes dramatic bilaminar transformation between 13 and 15 postconceptional weeks (PCW), followed by subtle sublamination in three 'floors' (deep, intermediate, superficial) of midgestation (15-21 PCW). During the stationary phase (22-28 PCW), SP persists as a trilaminar compartment, gradually losing its sublaminar organization towards the end of gestation and remains as a single layer of SP remnant in the newborn brain. Based on these sublaminar transformations, we have documented developmental changes in the distribution, maturational gradients and expression of molecular markers in SP synapses, transitional forms of astroglia, neurons and ECM, which occur concomitantly with the ingrowth of thalamo-cortical, basal forebrain and cortico-cortical axons in a deep to superficial fashion. The deep SP is the zone of ingrowing axons - 'entrance (ingrowth) zone'. The process of axonal ingrowth begins with thalamo-cortical fibers and basal forebrain afferents, indicating an oblique geometry. During the later fetal period, deep SP receives long cortico-cortical axons exhibiting a tangential geometry. Intermediate SP ('proper') is the navigation and 'nexus' sublamina consisting of a plexiform arrangement of cellular elements providing guidance and substrate for axonal growth, and also containing transient connectivity of dendrites and axons in a tangential plane without radial boundaries immersed in an ECM-rich continuum. Superficial SP is the axonal accumulation ('waiting compartment') and target selection zone, indicating a dense distribution of synaptic markers, accumulation of thalamo-cortical axons (around 20 PCW), overlapping with dendrites from layer VI neurons. In the late preterm brain period, superficial SP contains a chondroitin sulfate non-immunoreactive band. The developmental dynamics for the distribution of neuronal, glial and ECM markers comply with sequential ingrowth of afferents in three levels of SP: ECM and synaptic markers shift from deep to superficial SP, with transient forms of glia following this arrangement, and calretinin neurons are concentrated in the SP during the formation phase. These results indicate developmental and morphogenetic roles in the SP cellular (transient glia, neurons and synapses) and ECM framework, enabling the spatial accommodation, navigation and establishment of numerous connections of cortical pathways in the expanded human brain. The original findings of early developmental dynamics of transitional subtypes of astroglia, calretinin neurons, ECM and synaptic markers presented in the SP are interesting in the light of recent concepts concerning its functional and morphogenetic role and an increasing interest in SP as a prospective substrate of abnormalities in cortical circuitry, leading to a cognitive deficit in different neurodevelopmental disorders.
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http://dx.doi.org/10.1111/joa.12920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704274PMC
September 2019

Interactive histogenesis of axonal strata and proliferative zones in the human fetal cerebral wall.

Brain Struct Funct 2018 Dec 9;223(9):3919-3943. Epub 2018 Aug 9.

Croatian Institute for Brain Research, Centar of Research Excellence for Basic, Clinical and Translational Neuroscience, University of Zagreb, School of Medicine, Zagreb, Croatia.

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 axonal sagittal strata (SS) and their relationship with proliferative zones in a series of human brains (8-40 post-conceptional weeks; PCW) by comparing histological, histochemical, and immunocytochemical data with magnetic resonance imaging (MRI). Between 8.5 and 11 PCW, thalamocortical fibers from the intermediate zone (IZ) were initially dispersed throughout the subventricular zone (SVZ), while sizeable axonal "invasion" occurred between 12.5 and 15 PCW followed by callosal fibers which "delaminated" the ventricular zone-inner SVZ from the outer SVZ (OSVZ). During midgestation, the SS extensively invaded the OSVZ, separating cell bands, and a new multilaminar axonal-cellular compartment (MACC) was formed. Preterm period reveals increased complexity of the MACC in terms of glial architecture and the thinning of proliferative bands. The addition of associative fibers and the formation of the centrum semiovale separated the SS from the subplate. In vivo MRI of the occipital SS indicates a "triplet" structure of alternating hypointense and hyperintense bands. Our results highlighted the developmental continuity of sagittally oriented "corridors" of projection, commissural and associative fibers, and histogenetic interaction with progenitors, neurons, and glia. Histogenetical changes in the MACC, and consequently, delineation of the SS on MRI, may serve as a relevant indicator of white matter microstructural integrity in the developing brain.
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http://dx.doi.org/10.1007/s00429-018-1721-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267252PMC
December 2018

Coevolution in the timing of GABAergic and pyramidal neuron maturation in primates.

Proc Biol Sci 2017 Aug;284(1861)

Evolutionary Neuroscience Group, Department of Psychology, Cornell University, Ithaca, NY, USA.

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 86 developing primate and rodent brains. We use high-resolution structural, diffusion MR scans and histological material to compare the timing of the ganglionic eminences (GE) and cortical proliferative pool (CPP) maturation between humans, macaques, rats, and mice. We also compare the timing of post-neurogenetic maturation of GABAergic and pyramidal neurons in primates (i.e. humans, macaques) relative to rats and mice to identify whether delays in neurogenesis are concomitant with delayed post-neurogenetic maturation. We found that the growth of the GE and CPP are both selectively delayed compared with other events in primates. By contrast, the timing of post-neurogenetic GABAergic and pyramidal events (e.g. synaptogenesis) are predictable from the timing of other events in primates and in studied rodents. The extended duration of GABAergic and pyramidal neuron production is associated with the amplification of GABAerigc and pyramidal neuron numbers in the human and non-human primate cortex.
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http://dx.doi.org/10.1098/rspb.2017.1169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577486PMC
August 2017

Spatiotemporal Relationship of Brain Pathways during Human Fetal Development Using High-Angular Resolution Diffusion MR Imaging and Histology.

Front Neurosci 2017 11;11:348. Epub 2017 Jul 11.

Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical SchoolBoston, MA, United States.

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 postmortem human fetal brains [ = 9, age = 18-34 post-conceptual weeks (PCW)] that were grossly normal with no pathologic abnormalities. After HARDI was performed, the fibers were reconstructed using Q-ball algorithm and deterministic streamline tractography. The position of major fiber pathways within transient fetal zones was identified both on diffusion weighted images and on histological sections. Our major findings include: (1) the development of massive projection fibers by 18 PCW, as compared to most association fibers (with the exception of limbic fibers) which have only begun to emerge, (2) the characteristic laminar distribution and sagittal plane geometry of reconstructed fibers throughout development, (3) the protracted prenatal development shown of the corpus collosum and its' associated fibers, as well as the association fibers, and (4) the predomination of radial coherence in the telencephalon (i.e., majority of streamlines in the telencephalic wall were radially oriented) during early prenatal period (24 PCW). In conclusion, correlation between histology and HARDI (in combination with Q-ball reconstruction and deterministic streamline tractography) allowed us to detect sequential development of fiber systems (projection, callosal, and association), their spatial relations with transient fetal zones, and their geometric properties.
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http://dx.doi.org/10.3389/fnins.2017.00348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504538PMC
July 2017

Growth of Thalamocortical Fibers to the Somatosensory Cortex in the Human Fetal Brain.

Front Neurosci 2017 27;11:233. Epub 2017 Apr 27.

Department of Neuroscience, Croatian Institute for Brain Research, School of Medicine, University of ZagrebZagreb, Croatia.

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 selection, and ingrowth in the cortical plate (CP) using histological sections from post-mortem fetal brain [from 7 to 34 postconceptional weeks (PCW)] that were processed with acetylcholinesterase (AChE) histochemistry and immunohistochemical methods. Images were compared with post mortem diffusion tensor imaging (DTI)-based fiber tractography (code No NO1-HD-4-3368). The results showed TH-C axon outgrowth occurs as early as 7.5 PCW in the ventrolateral part of the thalamic anlage. Between 8 and 9.5 PCW, TH-C axons form massive bundles that traverse the diencephalic-telencephalic boundary. From 9.5 to 11 PCW, thalamocortical axons pass the periventricular area at the pallial-subpallial boundary and enter intermediate zone in radiating fashion. Between 12 and 14 PCW, the TH-C axons, aligned along the fibers from the basal forebrain, continue to grow for a short distance within the deep intermediate zone and enter the deep CP, parallel with SP expansion. Between 14 and 18 PCW, the TH-C interdigitate with callosal fibers, running shortly in the sagittal stratum and spreading through the deep SP ("waiting" phase). From 19 to 22 PCW, TH-C axons accumulate in the superficial SP below the somatosensory cortical area; this occurs 2 weeks earlier than in the frontal and occipital cortices. Between 23 and 24 PCW, AChE-reactive TH-C axons penetrate the CP concomitantly with its initial lamination. Between 25 and 34 PCW, AChE reactivity of the CP exhibits an uneven pattern suggestive of vertical banding, showing a basic 6-layer pattern. In conclusion, human thalamocortical axons show prolonged growth (4 months), and somatosensory fibers precede the ingrowth of fibers destined for frontal and occipital areas. The major features of growing TH-C somatosensory fiber trajectories are fan-like radiation, short runs in the sagittal strata, and interdigitation with the callosal system. These results support our hypothesis that TH-C axons are early factors in SP and CP morphogenesis and synaptogenesis and may regulate cortical somatosensory system maturation.
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http://dx.doi.org/10.3389/fnins.2017.00233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5406414PMC
April 2017

Secondary expansion of the transient subplate zone in the developing cerebrum of human and nonhuman primates.

Proc Natl Acad Sci U S A 2016 08 8;113(35):9892-7. Epub 2016 Aug 8.

Department of Neuroscience, Yale University, New Haven, CT 06510; Kavli Institute for Neuroscience, School of Medicine, Yale University, New Haven, CT 06510;

The subplate (SP) was the last cellular compartment added to the Boulder Committee's list of transient embryonic zones [Bystron I, Blakemore C, Rakic P (2008) Nature Rev Neurosci 9(2):110-122]. It is highly developed in human and nonhuman primates, but its origin, mode, and dynamics of development, resolution, and eventual extinction are not well understood because human postmortem tissue offers only static descriptive data, and mice cannot serve as an adequate experimental model for the distinct regional differences in primates. Here, we take advantage of the large and slowly developing SP in macaque monkey to examine the origin, settling pattern, and subsequent dispersion of the SP neurons in primates. Monkey embryos exposed to the radioactive DNA replication marker tritiated thymidine ([(3)H]dT, or TdR) at early embryonic ages were killed at different intervals postinjection to follow postmitotic cells' positional changes. As expected in primates, most SP neurons generated in the ventricular zone initially migrate radially, together with prospective layer 6 neurons. Surprisingly, mostly during midgestation, SP cells become secondarily displaced and widespread into the expanding SP zone, which becomes particularly wide subjacent to the association cortical areas and underneath the summit of its folia. We found that invasion of monoamine, basal forebrain, thalamocortical, and corticocortical axons is mainly responsible for this region-dependent passive dispersion of the SP cells. Histologic and immunohistochemical comparison with the human SP at corresponding fetal ages indicates that the same developmental events occur in both primate species.
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http://dx.doi.org/10.1073/pnas.1610078113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024589PMC
August 2016

Quantitative and Qualitative Analysis of Transient Fetal Compartments during Prenatal Human Brain Development.

Front Neuroanat 2016 24;10:11. Epub 2016 Feb 24.

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

The cerebral wall of the human fetal brain is composed of transient cellular compartments, which show characteristic spatiotemporal relationships with intensity of major neurogenic events (cell proliferation, migration, axonal growth, dendritic differentiation, synaptogenesis, cell death, and myelination). The aim of the present study was to obtain new quantitative data describing volume, surface area, and thickness of transient compartments in the human fetal cerebrum. Forty-four postmortem fetal brains aged 13-40 postconceptional weeks (PCW) were included in this study. High-resolution T1 weighted MR images were acquired on 19 fetal brain hemispheres. MR images were processed using in-house software (MNI-ACE toolbox). Delineation of fetal compartments was performed semi-automatically by co-registration of MRI with histological sections of the same brains, or with the age-matched brains from Zagreb Neuroembryological Collection. Growth trajectories of transient fetal compartments were reconstructed. The composition of telencephalic wall was quantitatively assessed. Between 13 and 25 PCW, when the intensity of neuronal proliferation decreases drastically, the relative volume of proliferative (ventricular and subventricular) compartments showed pronounced decline. In contrast, synapse- and extracellular matrix-rich subplate compartment continued to grow during the first two trimesters, occupying up to 45% of telencephalon and reaching its maximum volume and thickness around 30 PCW. This developmental maximum coincides with a period of intensive growth of long cortico-cortical fibers, which enter and wait in subplate before approaching the cortical plate. Although we did not find significant age related changes in mean thickness of the cortical plate, the volume, gyrification index, and surface area of the cortical plate continued to exponentially grow during the last phases of prenatal development. This cortical expansion coincides developmentally with the transformation of embryonic cortical columns, dendritic differentiation, and ingrowth of axons. These results provide a quantitative description of transient human fetal brain compartments observable with MRI. Moreover, they will improve understanding of structural-functional relationships during brain development, will enable correlation between in vitro/in vivo imaging and fine structural histological studies, and will serve as a reference for study of perinatal brain injuries.
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http://dx.doi.org/10.3389/fnana.2016.00011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764715PMC
March 2016

Neural ECM in laminar organization and connectivity development in healthy and diseased human brain.

Prog Brain Res 2014 ;214:159-78

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

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 contain large amounts and a diversity of extracellular matrix components, which are especially prominent in the transient subplate zone, in the crossroads of axonal pathways, at the developing cortical-white matter interface, and in the marginal zone. Perinatal and postnatal reorganizations of these tissue compartments extend into the second year of life. Developmental changes in the amount and composition of the extracellular matrix (as well as changes in fiber architectonics) are significant for plastic responses to damage and for changes in magnetic resonance imaging (MRI) signal intensity of the fetal and early postnatal human brain. In this chapter, we discuss the expression pattern of the major components of the fetal ECM of the human brain and the role they play during laminar and connectivity development in healthy brain and in the neurodevelopmental disorders. The aim of the chapter is to elucidate ECM-related developmental events as potential models of successful functional recovery after injury and to explore its relevance for diagnostic and therapeutic approaches.
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http://dx.doi.org/10.1016/B978-0-444-63486-3.00007-4DOI Listing
August 2015

The relevance of human fetal subplate zone for developmental neuropathology of neuronal migration disorders and cortical dysplasia.

CNS Neurosci Ther 2015 Feb 14;21(2):74-82. Epub 2014 Oct 14.

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

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 fetal cortical circuitry. Thus, the subplate has an important but hitherto neglected role in the human fetal cortical connectome. The subplate is also an important compartment for radial and tangential migration of future cortical neurons. We review the diversity of subplate neuronal phenotypes and their involvement in cortical circuitry and discuss the complexity of late neuronal migration through the subplate as well as its potential relevance for pathogenesis of migration disorders and cortical dysplasia. While migratory neurons may become misplaced within the subplate, they can easily survive by being involved in early subplate circuitry; this can enhance their subsequent survival even if they have immature or abnormal physiological activity and misrouted connections and thus survive into adulthood. Thus, better understanding of subplate developmental history and various subsets of its neurons may help to elucidate certain types of neuronal disorders, including those accompanied by epilepsy.
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http://dx.doi.org/10.1111/cns.12333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495198PMC
February 2015

Developmental dynamics of radial vulnerability in the cerebral compartments in preterm infants and neonates.

Front Neurol 2014 29;5:139. Epub 2014 Jul 29.

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

The developmental vulnerability of different classes of axonal pathways in preterm white matter is not known. We propose that laminar compartments of the developing cerebral wall serve as spatial framework for axonal growth and evaluate potential of anatomical landmarks for understanding reorganization of the cerebral wall after perinatal lesions. The 3-T MRI (in vivo) and histological analysis were performed in a series of cases ranging from 22 postconceptional weeks to 3 years. For the follow-up scans, three groups of children (control, normotypic, and preterms with lesions) were examined at the term equivalent age and after the first year of life. MRI and histological abnormalities were analyzed in the following compartments: (a) periventricular, with periventricular fiber system; (b) intermediate, with periventricular crossroads, sagittal strata, and centrum semiovale; (c) superficial, composed of gyral white matter, subplate, and cortical plate. Vulnerability of thalamocortical pathways within the crossroads and sagittal strata seems to be characteristic for early preterms, while vulnerability of long association pathways in the centrum semiovale seems to be predominant feature of late preterms. The structural indicator of the lesion of the long association pathways is the loss of delineation between centrum semiovale and subplate remnant, which is possible substrate of the diffuse periventricular leukomalacia. The enhanced difference in MR signal intensity of centrum semiovale and subplate remnant, observed in damaged children after first year, we interpret as structural plasticity of intact short cortico-cortical fibers, which grow postnatally through U-zones and enter the cortex through the subplate remnant. Our findings indicate that radial distribution of MRI signal abnormalities in the cerebral compartments may be related to lesion of different classes of axonal pathways and have prognostic value for predicting the likely outcome of prenatal and perinatal lesions.
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http://dx.doi.org/10.3389/fneur.2014.00139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114264PMC
August 2014

Involvement of the subplate zone in preterm infants with periventricular white matter injury.

Brain Pathol 2014 03 18;24(2):128-41. Epub 2014 Feb 18.

Inserm U676, Paris; Croatian Institute for Brain Research, Medical School, University of Zagreb, Zagreb.

Studies of periventricular white matter injury (PWMI) in preterm infants suggest the involvement of the transient cortical subplate zone. We studied the cortical wall of noncystic and cystic PWMI cases and controls. Non-cystic PWMI corresponded to diffuse white matter lesions, the predominant injury currently detected by imaging. Glial cell populations were analyzed in post-mortem human frontal lobes from very preterm [24–29 postconceptional weeks (pcw)] and preterm infants (30–34 pcw) using immunohistochemistry for glial fibrillary acidic protein (GFAP), monocarboxylate transporter 1(MCT1), ionized calcium-binding adapter molecule 1 (Iba1), CD68 and oligodendrocyte lineage (Olig2). Glial activation extended into the subplate in non-cystic PWMI but was restricted to the white matter in cystic PWMI. Two major age-related and laminar differences were observed in non-cystic PWMI: in very preterm cases, activated microglial cells were increased and extended into the subplate adjacent to the lesion, whereas in preterm cases, an astroglial reaction was seen not only in the subplate but throughout the cortical plate. There were no differences in Olig2-positive pre-oligodendrocytes in the subplate inPWMI cases compared with controls. The involvement of gliosis in the deep subplate supports the concept of the complex cellular vulnerability of the subplate zone during the preterm period and may explain widespread changes in magnetic resonance signal intensity in early PWMI.
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http://dx.doi.org/10.1111/bpa.12096DOI Listing
March 2014

The significance of the subplate for evolution and developmental plasticity of the human brain.

Front Hum Neurosci 2013 2;7:423. Epub 2013 Aug 2.

Section of Developmental Neuroscience, Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine Zagreb, Croatia.

The human life-history is characterized by long development and introduction of new developmental stages, such as childhood and adolescence. The developing brain had important role in these life-history changes because it is expensive tissue which uses up to 80% of resting metabolic rate (RMR) in the newborn and continues to use almost 50% of it during the first 5 postnatal years. Our hominid ancestors managed to lift-up metabolic constraints to increase in brain size by several interrelated ecological, behavioral and social adaptations, such as dietary change, invention of cooking, creation of family-bonded reproductive units, and life-history changes. This opened new vistas for the developing brain, because it became possible to metabolically support transient patterns of brain organization as well as developmental brain plasticity for much longer period and with much greater number of neurons and connectivity combinations in comparison to apes. This included the shaping of cortical connections through the interaction with infant's social environment, which probably enhanced typically human evolution of language, cognition and self-awareness. In this review, we propose that the transient subplate zone and its postnatal remnant (interstitial neurons of the gyral white matter) probably served as the main playground for evolution of these developmental shifts, and describe various features that makes human subplate uniquely positioned to have such a role in comparison with other primates.
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http://dx.doi.org/10.3389/fnhum.2013.00423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731572PMC
August 2013

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

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

Epigenetic regulation of fetal brain development and neurocognitive outcome.

Proc Natl Acad Sci U S A 2012 Jul 2;109(28):11062-3. Epub 2012 Jul 2.

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

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http://dx.doi.org/10.1073/pnas.1208085109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396521PMC
July 2012

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

Pineal cysts - a benign consequence of mild hypoxia in a near-term brain?

Neuro Endocrinol Lett 2011 ;32(5):663-6

Department of Pediatric Neurology, University Medical Centre, Ljubljana, Slovenia.

Background: Pineal cysts are benign glial uniloculated or multiloculated fluid-filled sacs located in the pineal gland region. Small pineal cysts are often found incidentally in healthy adults in 1.5-10.8%. Large cysts may cause neurological problems due to pressure exertion on adjacent structures.

Methods: We have used prospective, observational study of an inception cohort of 16 adolescents of mean age 21.69 years (SD=±0.87) with mild (68.7%) to moderate (31.3%) HIE: 7 girls (43.8%) and 9 (56.3%) boys, born with mean gestational age of 35.75 weeks (SD=±3.80) and mean birthweight of 2 644 g (SD=±815). HIE was confirmed by presence of abnormal CTG and/or meconium and/or Apgar scores less than 7 at 5 minutes and/or need for resuscitation and/or cord pH less than 7.2 and /or BE more than -15. The clinical assessment of HIE was done according to the Sarnat-Sarnat scoring. Neonatal data, including EEG and imaging data, were collected. Adolescents were scanned with 3T Magnetom Trio Tim, Siemens, head coil 12 channels, regular sequences and sagittal 3D magnetization-prepared rapid acquisition gradient echo (MPRAGE) sequence with voxel size 1 mm3. Neurological outcome was determined.

Results: In 1 patient we found cortical dysplasia and 1 had a panic attack hence their data were omitted. In the group of 14 we have incidentally found in 5 patients a larger, asymptomatic pineal cysts with the overall incidence of 36%. Other MR findings in the group were in 50% white matter injury, in 50% thinner corpus callosum. No statistically significant difference between neonatal cUS and late follow-up MRI (p=0.881) was found. Correlation was not significant with Spearman correlation coefficient 0.201. Presence of pineal cysts was linked to thinner corpus callosum (p=0.005).

Conclusions: We propose that larger pineal cyst, in the absence of other imaging findings except for thinner corpus callosum, is a benign consequence of mild hypoxia in a near-term brain. Our findings warrant a larger study.
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March 2012

Extraordinary neoteny of synaptic spines in the human prefrontal cortex.

Proc Natl Acad Sci U S A 2011 Aug 25;108(32):13281-6. Epub 2011 Jul 25.

Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10,000 Zagreb, Croatia.

The major mechanism for generating diversity of neuronal connections beyond their genetic determination is the activity-dependent stabilization and selective elimination of the initially overproduced synapses [Changeux JP, Danchin A (1976) Nature 264:705-712]. The largest number of supranumerary synapses has been recorded in the cerebral cortex of human and nonhuman primates. It is generally accepted that synaptic pruning in the cerebral cortex, including prefrontal areas, occurs at puberty and is completed during early adolescence [Huttenlocher PR, et al. (1979) Brain Res 163:195-205]. In the present study we analyzed synaptic spine density on the dendrites of layer IIIC cortico-cortical and layer V cortico-subcortical projecting pyramidal neurons in a large sample of human prefrontal cortices in subjects ranging in age from newborn to 91 y. We confirm that dendritic spine density in childhood exceeds adult values by two- to threefold and begins to decrease during puberty. However, we also obtained evidence that overproduction and developmental remodeling, including substantial elimination of synaptic spines, continues beyond adolescence and throughout the third decade of life before stabilizing at the adult level. Such an extraordinarily long phase of developmental reorganization of cortical neuronal circuitry has implications for understanding the effect of environmental impact on the development of human cognitive and emotional capacities as well as the late onset of human-specific neuropsychiatric disorders.
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http://dx.doi.org/10.1073/pnas.1105108108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156171PMC
August 2011

Jelena Krmpotić-Nemanić (1921-2008): contributions to human neuroanatomy.

Coll Antropol 2011 Jan;35 Suppl 1:345-9

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

Jelena Krmpotić-Nemanić (1921-2008) was a world-famous anatomist, internationally distinguished otolaryngologist, a member of the Croatian Academy of Sciences & Arts and appreciated professor at the School of Medicine University of Zagreb. The founding influence in her scientific career came from her mentor Drago Perovid who was a student of Ferdinand Hochstetter, the leading authority in the field of human developmental neuroanatomy and embryology. Such an influence was obviously important in early shaping of the research agenda of Jelena Krmpotić-Nemanić, and it remains important in a long series of studies on developing human telencephalon initiated by Ivica Kostović and his collaborators - with an always present and active support of Jelena Krmpotić-Nemanić. The aim of this mini review is to briefly describe her numerous contributions to the anatomy of the human peripheral and central nervous system.
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January 2011

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

Prominent periventricular fiber system related to ganglionic eminence and striatum in the human fetal cerebrum.

Brain Struct Funct 2011 Jan 15;215(3-4):237-53. Epub 2010 Oct 15.

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

Periventricular pathway (PVP) system of the developing human cerebrum is situated medial to the intermediate zone in the close proximity to proliferative cell compartments. In order to elucidate chemical properties and developing trajectories of the PVP we used DTI in combination with acetylcholinesterase histochemistry, SNAP-25 immunocytochemistry and axonal cytoskeletal markers (SMI312, MAP1b) immunocytochemistry on postmortem paraformaldehyde-fixed brains of 30 human fetuses ranging in age from 10 to 38 postconceptional weeks (PCW), 2 infants (age 1-3 months) and 1 adult brain. The PVP appears in the early fetal period (10-13 PCW) as two defined fibre bundles: the corpus callosum (CC) and the fetal fronto-occipital fascicle (FOF). In the midfetal period (15-18 PCW), all four components of the PVP can be identified: (1) the CC, which at rostral levels forms a voluminous callosal plate; (2) the FOF, with SNAP-25-positive fibers; (3) the fronto-pontine pathway (FPP) which for a short distance runs within the PVP; and (4) the subcallosal fascicle of Muratoff (SFM) which contains cortico-caudate projections. The PVPs are situated medial to the internal capsule at the level of the cortico-striatal junction; they remain prominent during the late fetal and early preterm period (19-28 PCW) and represent a portion of the wider periventricular crossroad of growing associative, callosal and projection pathways. In the perinatal period, the PVPs change their topographical relationships, decrease in size and the FOF looses its SNAP-25-reactivity. In conclusion, the hitherto undescribed PVP of the human fetal cerebrum contains forerunners of adult associative and projection pathways. Its transient chemical properties and relative exuberance suggest that the PVP may exert influence on the development of cortical connectivity (intermediate targeting) and other neurogenetic events such as neuronal proliferation. The PVP's topographical position also indicates that it is a major site of vulnerability in hypoxic-ischaemic perinatal brain injury.
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http://dx.doi.org/10.1007/s00429-010-0279-4DOI Listing
January 2011