In vitro MRI of brain development

European Journal of Radiology 57 (2006) 187–198

In vitro MRI of brain development

Marko Radosa,b, Milos Judasa, Ivica Kostovica,∗a Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 12, 10000 Zagreb, Croatiab Clinical Hospital Center Zagreb, School of Medicine, University of Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia

Received 11 November 2005; received in revised form 14 November 2005; accepted 16 November 2005

Abstract

In this review, we demonstrate the developmental appearance, structural features, and reorganization of transient cerebral zones and structuresin the human fetal brain using a correlative histological and MRI analysis. The analysis of postmortem aldehyde-fixed specimens (age range:10 postovulatory weeks to term) revealed that, at 10 postovulatory weeks, the cerebral wall already has a trilaminar appearance and consistsof: (1) a ventricular zone of high cell-packing density; (2) an intermediate zone; (3) the cortical plate (in a stage of primary consolidation)with high MRI signal intensity. The anlage of the hippocampus is present as a prominent bulging in the thin limbic telencephalon. The earlyfetal telencephalon impar also contains the first commissural fibers and fornix bundles in the septal area. The ganglionic eminence is clearlyv . The mostm

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isible as an expanded continuation of the proliferative ventricular zone. The basal ganglia showed an initial aggregation of cellsassive fiber system is in the hemispheric stalk, which is in continuity with thalamocortical fibers.During the mid-fetal period (15–22 postovulatory weeks), the typical fetal lamination pattern develops and the cerebral wa

f the following zones: (a) a marginal zone (visible on MRI exclusively in the hippocampus); (b) the cortical plate with higacking density and high MRI signal intensity; (c) the subplate zone, which is the most prominent zone rich in extracellular mith a very low MRI signal intensity; (d) the intermediate zone (fetal “white matter”); (e) the subventricular zone; (f) the perilar fiber-rich zone; (g) the ventricular zone. The ganglionic eminence is still a very prominent structure with an intense proctivity.During the next period (22–26 postovulatory weeks), there is the developmental peak of transient MRI features, caused b

ontent of hydrophyllic extracellular matrix in the subplate zone and the accumulation of waiting afferent axons. The period7 and 30 postovulatory weeks is characterized by gradual blurring of the laminar structure in parallel with the formationral convolutions. In near-term preterm infants, T2-weighted MR images showed better contrast resolution than T1-weightee conclude that transient fetal zones and subcortical structures display characteric MRI features due to the high content o

ular matrix in the subplate zone, higher MRI signal intensity of zones with high cell-packing intensity, and the presence ofbers.2005 Elsevier Ireland Ltd. All rights reserved.

eywords: Subplate zone; Periventricular crossroads; Preterm infant

. Introduction

The developing cerebral wall consists of transient fetalones [1,2], i.e., laminar architectonic compartments inhich major cellular events (proliferation, migration, celleath, outgrowth of axons, synaptogenesis) occur according

o a specific timetable[3]. These transient fetal zones can

∗ Corresponding author. Tel.: +385 1 4596 902; fax: +385 1 4596 942.E-mail address: [email protected] (I. Kostovic).

be visualized on both in vitro[1,4] and in vivo MR image[2,5–7]. In addition, MRI opens new possibilities for analyof structural maturation of the fetal brain[8] and for identi-fication of abnormalities and follow-up of structural plaschanges in response to perinatal brain damage[6,9–14]. How-ever, the precise correlation of these MR images with findin histological sections is required for the proper interprtion of prenatal laminar development of the human cerebas revealed by MRI[1,2,15]. In this review, we demonstrathe scope and possibilities of correlative histological

720-048X/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.ejrad.2005.11.019

188 M. Rados et al. / European Journal of Radiology 57 (2006) 187–198

MRI analysis in describing the development of the humancerebrum from 10 postovulatory weeks (POW) to the termbirth.

2. The early fetal telencephalon (10–13 POW)

All major parts of the early human fetal telencephalonare clearly visible in both histological and MRI sections (theyoungest specimen analyzed is 10 POW).

2.1. Laminar pattern—trilaminar appearance of thecerebral wall and the primary consolidation of thecortical plate

The midlateral part of the cerebral wall (Fig. 1A) is consid-erably thicker than its dorsal or medial/limbic parts, and threefetal zones can be clearly delineated in both histological andMRI sections (from the ventricles to the pial surface): (a) theventricular zone, characterized by high cell-packing densityin Nissl-stained sections (Fig. 1A) and a high-intensity MRIsignal in T1-weighted MRI scans (Fig. 1B); (b) the interme-diate zone of moderate MRI signal intensity (Fig. 1B), withsomewhat higher MRI signal intensity in its deep part, whichcorresponds to the proliferative subventricular zone in Nissl-stained sections; (c) the cortical plate of high MRI signali imea s ofp pres-e thisz er-h ved,w

which, in older fetuses of that age group, appears as a realcurvature (Fig. 2A and B).

2.2. Midline structures—telencephalon impar andcommissural plate

The midline structures during this time are at the onsetof their development. The commissural plate is a thickeneddorsal part of the telencephalon impar, in which the firstcommissural fibres cross the midline. Two fornix bundlesmerge toward the septal area (Fig. 1A), and thus, contributeto the triangular shape of the telencephalon impar in MRIscans (Figs. 1A and 2B, double arrows). In fetuses olderthan 11 POW, the major event is the appearance of the cor-pus callosum in the dorsal part of the commissural plate(Fig. 2A–D).

2.3. Ganglionic eminence and basal ganglia

The most prominent basal telencephalic structure is theganglionic eminence, which represents a prominent regionalthickening of the ventricular zone (Figs. 1A, B and 2A, D),and thus, is also characterized by high cell-packing density(Fig. 2A and C) and high MRI signal intensity (Fig. 2Band D). The ganglionic eminence is the site of origin forneurons of the basal ganglia, certain thalamic neurons, andGl ecog-n as ap gnali sl-s rics log-

F (A) and A) anw Z), theo lionic e s in this as callos ortical platG S = he = putamenP e; T or

ntensity, which undergoes its first consolidation at this tnd thus consists of tightly packed ontogenetic columnostmigratory neurons. Histological sections reveal thence of the most superficial, marginal zone; however,one is too thin to be visualized by MRI. The limbic, intemispheric cortex is thinner and already slightly curith visible bulging of the hippocampus (Fig. 1A and B),

ig. 1. Trilaminar organization of the early human cerebral wall, at 10eighted MRI (B). The cerebral wall consists of the ventricular zone (Vf the hippocampus (hip), commissural plate (double arrows), gangubsequent figures: A = amygdala; C = caudate nucleus; CC = corpus= ganglionic eminence; GP = globus pallidus; Hip = hippocampus; HC = plexus chorioideus; SP = subplate zone; SZ = subventricular zon

ABAergic interneurons of the cerebral cortex[3]. At rostralevels, the head of the developing caudate nucleus is rizable within the concavity of the ganglionic eminenceoorly delineated area of significantly decreased MRI si

ntensity (Fig. 2D); however, it is clearly delineated in Nistained sections (Fig. 2A and C). Although the hemisphetalk and the internal capsule are well-developed in histo

10.5 (B) postovulatory weeks (POW), as revealed by Nissl staining (d T1-intermediate zone (IZ) and the cortical plate (CP). Note, the early differentiationminence (G), caudate nucleus (C), and putamen (P). Abbreviationnd

um; CF = calcarine fissure; CGL = corpus geniculatum laterale; CP = ce;mispheric stalk; IC or CI = internal capsule; IZ = intermediate zone; P;TH = thalamus; VZ = ventricular zone.

M. Rados et al. / European Journal of Radiology 57 (2006) 187–198 189

Fig. 2. Semi-horizontal Nissl-stained (A and C) and T1-weighted MRI sections (B and D) through the telencephalon of 11.5 (A and C) and 12.5 (B and D)postovulatory week-old fetuses. Note that the trilaminar organization of the cerebral wall, the ganglionic eminence with developing caudate and putamen, andthe hippocampal anlage (arrow) are all clearly visible on both histological and MRI sections. However, the hemispheric stalk (HS) is clearly visibleonly inhistological sections. Double arrows in B point to the commissural plate.

ical sections (Fig. 2A and C), they are poorly delineated onMRI scans. Lateral to the internal capsule, the putamen isclearly delineated in histological sections (Fig. 2A and C),but less clearly visible in MRI scans and stretches towardthe basal telencephalic region, which is characterized by

decreased MRI signal intensity while the external capsulemarks its border with the intermediate zone. At this age, thecorpus amygdaloideum is still a poorly delineated cellularmass located anterior to the ventral part of the hippocampalanlage.


Fig. 3. Typical fetal lamination pattern as revealed in horizontal MRI (A and C) and Nissl-stained (B and D) sections through the cerebrum of fetuses aged 18POW (A–C) and 20.5 POW (D). In addition to transient fetal zones (CP, SP, IZ, VZ), note the presence of the periventricular fiber-rich zone (asterisks) and theperiventricular crossroads (arrows) of the growing axonal pathways.

2.4. Organization of major fiber systems

Three fiber systems are recognizable at this early age:the corpus callosum, the fornix, and the cerebral stalk(Hemispharenstiel). The cerebral stalk is a characteristic fea-ture of early brain development and is still visible in theyoungest specimens (Fig. 2A and C). It represents a massiveconnection between the telencephalon and the diencephalon(thalamus) and contains all the projection fibres of the devel-

oping internal capsule, including the thalamocortical fibersas the main component.

3. The cerebral wall in the mid-fetal period (15–22POW)

The mid-fetal period (15–22 POW) is characterized by thedevelopment of the transient subplate zone and the presenceof the typical fetal lamination pattern.


3.1. Laminar pattern

The following fetal zones are present in the pia-to-ventricles direction (Fig. 3A and D): the marginal zone;the cortical plate; the subplate zone; the intermediate zone;the subventricular zone; the fiber-rich periventricular zone

(Fig. 3A–D, asterisks); the ventricular zone. Whereas, themost superficial marginal zone is too thin to be visu-alized in MRI scans, the cortical plate, composed ofdensely packed postmigratory neurons arranged in verti-cal ontogenetic columns, is sharply delineated in both his-tological (Figs. 3B, D and 4B, D, F) and MR images

FDiao

ig. 4. T1-weighted MRI (A, C, E) and Nissl-stained (B, D, F) coronal secti–F) reveal that, during the midfetal period, the cerebrum displays specific

n the calcarine fissure (CF) region; the fiber-rich periventricular zone (astermygdala (A and double arrows in C and D), and the cytoarchitectonic modun MRI scans (E). Arrowheads point to the external capsule, which marks th

ons through the cerebrum of fetuses aged 18 POW (C) and 20/21 POW (A, B,morphological features: the narrowing of the subplate zone (SP, betweenarrows)isks) within the subventricular (SZ) zone; the inhomogeneous appearance of theles in the striatum (F), which correspond to the patchy appearance of the striatume border between the intermediate (IZ) zone and the subplate (SP) zone.


(Figs. 3A, C and 4A, C, E). This stage is called the stage of thesecondary consolidation of the cortical plate. Below the cor-tical plate is a new and prominent transient fetal zone—thesubplate zone, which represents a “waiting” compartmentfor growing cortical afferents[16] and is characterized by avery large extracellular space[16], the abundant amount ofdifferent glycosaminoglycans and chondroitin sulfate pro-teoglycans in its extracellular matrix[1], and a very lowMRI signal intensity[1]. The external capsule marks theborder between the subplate zone and the intermediate zone(Fig. 4D–F, arrowheads), which is composed of large bun-dles of growing axons, migratory neurons, and immature glialcells, and which has a higher MRI signal intensity comparedto the subplate zone. The intermediate zone represents fetal“white matter”. Subsequently, the subventricular zone, whichis cellular in its outer part but becomes very fibrillar in itsinner part (toward the ventricle—asterisks inFig. 3B and D),transforms in the periventricular fiber-rich zone[1].

Transient fetal zones display clear regional differences inthickness and overall appearance. In the neocortical anlage,the most characteristic appearance is in the occipital visualcortex (Fig. 4A and B) where the calcarine fissure is alreadywell-pronounced, and, near the bottom, just the cortical plateis well developed, whereas, the subplate zone (as well as theintermediate and subventricular zones) becomes quite thin.In addition, the periventricular fiber-rich zone disappears att tioni or-t nd

mesocortical) regions are specified within the cerebral wall,and the entorhinal cortex already displays two main features:the lamina dissecans and the cellular islands (Fig. 5A and B).As the lamina dissecans has decreased MRI signal intensity(Fig. 5B, arrow), the position of the entorhinal region is rec-ognizable on MRI scans. Thus, MRI enables the tracing ofthe developmental history of at least two differentiating cor-tical areas: the entorhinal cortex[17] and the primary visualcortex. Finally, the ventricular zone is still prominent andcell-dense, which indicates an intense proliferative activity.

The hippocampal formation is an archicortical limbicregion, which also displays a characteristic convolutedappearance (Fig. 6D and E) and progressive narrowingof the cortical plate, corresponding to hippocampal areasCA2/CA3. However, the most interesting feature is theenlargement of the marginal zone. Namely, the hippocampalformation is the only part of the cerebral cortex in which themarginal zone is thick enough to be visualized by MRI and isobserved as a thin stripe of low MRI signal intensity super-ficial to the curved hippocampal cortical plate of high MRIsignal intensity. This thickening of the hippocampal marginalzone is related to transiently enlarged extracellular spaces,similar to the situation in the transient subplate zone[16].

3.2. Ganglionic eminence and basal ganglia

id-f ivelyt

F l cortical region can be easily recognized in both Nissl-stained (A) and MRI sections(

he bottom of the calcarine fissure, indicating a reducn the number of callosal fibers in the primary visual cex [16]. The main limbic (palaeocortical, archicortical, a

ig. 5. At 20 POW (A) or 25 POW (B), the early developing entorhina
B) due to the presence of characteristic lamina dissecans (arrows).
The ganglionic eminence is very prominent in the metal period, and can be followed as a direct (but progresshinner) continuation of the ventricular zone (Figs. 3–5) from


Fig. 6. At 21 POW (A, B, D, E) and at 24 POW (C), the subplate zone is very prominent in both histological (A, C, D) and MRI sections (B and E). The palesubplate zone (SP) in Nissl-stained sections (A and D) corresponds to the fibronectin-rich zone in immunohistochemical sections (C) and to the zone oflowMRI signal intensity in T1-weighted MR images (B and E). Cashew-shaped area (dotted line) in D and E corresponds to the region of the frontal periventricularcrossroads of the growing axonal pathways. Arrows in D and E point to the well-developed hippocampal formation, which has very thick marginal zone (lowerasterisk in D).

the level of the interventricular foramen to the temporal andoccipital horns of the lateral ventricles (Fig. 3A, B, D). Theanlage of the caudate nucleus (Figs. 3B, D and 4E, F) issituated in the concavity of the ganglionic eminence and ischaracterized by decreased MRI signal intensity. The head ofthe caudate is large and visible at the level of the interven-tricular foramen (Figs. 3B–D and 4E, F), while its tail is thinand well-delineated only on Nissl- and acetylcholinesterase-stained sections (Figs. 3B, D and 7A, C). On MR images, the

tail of the caudate merges with the fountainhead of the pos-terior limb of the internal capsule (Figs. 3C, 4C, and 6E). Inthe mid-fetal period, the corpus amygdaloideum develops itscharacteristic structure and, at coronal sections, appears asa large cellular mass that occupies the entire medial (lim-bic) part of the temporal lobe just frontomedially to thetip of the developing temporal horn of the lateral ventricles(Figs. 4C, D and 5A, B). The ventrolateral part of the amyg-dala is surrounded by a thin rim composed of the ventricular


Fig. 7. At 25 POW (B), 26 POW (A and C) and in full-term newborn (D), acetylcholinesterase histochemistry (A and C) and T1-weighted MRI scans (B andD) reveal that thalamocortical fibers from the thalamus (TH) and the lateral geniculate nucleus (CGL) acumulate in the upper subplate (SP) zone (A and C)and that the subplate zone gradually looses its characteristic MRI appearance and prominence (B and D). Note very well-developed hippocampal formation(arrows in B–D).

and subventricular zones (Fig. 4C and D, arrows), while thedorsolateral part of the amygdala is covered by a complexcrossroad of fibers[15] that originate from the inferior limb ofthe internal capsule, the anterior commissure, and the corpusamygdaloideum itself. Therefore, the corpus amygdaloidumis relatively well-delineated on MR images (Fig. 4C and B).However, as the corpus amygdaloideum is not a cytoarchitec-tonically homogeneous structure, but consists of a transient

barreloid formation[18], its appearance on MRI scans is alsononhomogeneous (Figs. 4C and 5B).

3.3. Ventricular system

The shape of the ventricular system is an important indi-cator of telencephalic maturation. In the mid-fetal period,the anterior horn of the lateral ventricle is rounded and pear-


shaped and has two angles rather than one. The dorsal anglemarks the transition of the upper to the lateral wall of the ven-tricle, and this is the forerunner of the future lateral angle. Theother angle marks the transition of the mid-fetal “lateral” wallto the ganglionic eminence, and thus, forms the “bottom” ofthe lateral ventricles.

3.4. Organization of fiber systems

The mid-fetal period is characterized by a substan-tial elaboration of major cerebral fiber systems. In Nissl-and acetylcholinesterase-stained sections, the corpus callo-sum is clearly delineated as an unstained periventricularregion in the roof and lateral wall of the lateral ventri-cles (Figs. 5A, 6A, D and 7A, C). It is also recognized onMRI scans as a periventricular region of low MRI signalintensity (Figs. 4C, E, 5B and 6E), which continues as aperiventricular fiber-rich zone wedged between the ventric-ular and subventricular zones. Below the corpus callosum,there is a well-developed fornix system that can be followedfrom the hippocampal alveus to the septal and mammillaryregions.

Although the corpus callosum, the internal capsule,and the external capsule continue to grow during themid-fetal period, their MRI delineation is relatively poor(Figs. 3C, 4C, E and 5B). The major systems of growingfi oads[ aract llularm y onT ndt heado ule,rp tter-w thep ntals

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subplate zone displays a low MRI signal intensity becauseit contains a hydrophyllic extracellular matrix rich in gly-cosaminoglycans, associated molecules (seeFig. 6C), andaxonal guidance cues[1]. The subplate zone retains theseprominent features up to 26 POW (Figs. 6B, C and 7B). Itslarge size, together with a characteristic MRI appearance,enable the in vivo visualization of this transient and impor-tant synaptic fetal zone[2,15]. The MRI visualization of thesubplate zone facilitates the analysis of developing corticalconnections in the human cerebrum[1] because the subplatezone contains the majority of cortical synapses and “wait-ing” afferent axons at this stage[16]. This offers a uniqueopportunity for structure–function correlation in late fetusesand preterm infants, because the subplate zone containstransiently arranged cortical afferents[16,20,21]and tran-sient thalamocortical synapses[22,23]. From 26 to 28 POWonward, the gradual disappearance of extracellular matrixfrom the subplate zone is correlated with gradual blurring ofits characteristic MRI signal intensity[1]. Thus, in vivo MRIvisualization of the subplate zone may serve as an essentialparameter in follow-up studies after perinatal periventricularleukomalacia and periventricular haemorrhage[1,15,24]. Itshould be noted that the intensity of the MRI signal is approxi-mately the same in the subplate zone and in the periventricularcrossroads (Figs. 6E and 7B).

After 26 POW, the MRI appearance of the cerebral wallc esses:( rticalc ticalc -u platez blur-r entg n thec lay-e nali thati

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bers intersect at the so-called periventricular crossr15]. There are at least six such crossroads, and all are cherized by the presence of abundant hydrophyllic extraceatrix, and thus, have decreased MRI signal intensit1-weighted images[15]. The main frontal crossroad a

he main posterior crossroad, located at the fountainf the anterior and posterior limb of the internal capsespectively, are quite prominent (Fig. 4B–D, arrows). Theosterior one is triangular and has been called a “Weinkel” [19], because its features are well-correlated withathological properties of this region in later developmetages.

. Developmental peaks of transient MRI features22–26 POW) and the subplate zone (27–30 POW)

The subplate zone attains its developmental peak, atn terms of thickness, between 27 and 30 POW (i.e., 29 anostmenstrual weeks). However, transient fetal MRI featf the cerebral wall reach their peak of prominence eaetween 22 and 26 POW.

.1. Laminar pattern

The cerebral wall still displays typical transient fetal zoventricular, periventricular fiber-rich, subventricular, inediate and subplate zone, the cortical plate, and the ma

one), and the subplate zone is the most prominent of allient zones (Figs. 6A–E and 7A). In T1-weighted images, th

-hanges substantially, as a consequence of several proca) development of the corona radiata system and coonvolutions that receive distal parts of the thalamocororona radiata fibers (Figs. 7A, C and 8A, B); (b) the gradal disappearance of extracellular matrix in both the subone and the periventricular crossroads, with correlateding of distinct MRI signal intensities; (c) the consequradual disappearance of a clear lamination pattern ierebral wall. The cortical plate gives rise to corticalrs II–VI, and retains its characteristically high MRI sig

ntensity, thus remaining the only laminar compartments well-delineated in MRI scans.

.2. Basal ganglia

The patchy MRI appearance of the striatum grally disappears (compareFig. 8A and B with Fig. 4End F) and its MRI signal becomes more homogenelthough the ventricular zone that covers the caudate nu

Figs. 8A, B and 9A) is still present, it is very thin and doot form the ganglionic eminence.

.3. Ventricular system

Whereas, the volume of white matter increases and coonvolutions begin to form, the volume of the ventricuystem progressively decreases and the anterior horn chts shape. Namely, the upper “mid-fetal” angle of the anteorn and the central part of the lateral ventricle disappnd, in the late fetus, just the lateral angle is present.


Fig. 8. In 34–36 POW preterm infants, both Nissl-stained (A) and T1-weighted MRI sections (B) reveal the gradual resolution of the transient subplatezone(between arrows in B). However, differences in histological staining (asterisk in A) and in MRI signal intensity (asterisk in B) demonstrate that thecrossroadsof growing pathways still contain a significant amount of hydrophyllic extracellular matrix.

Fig. 9. Near the term, the myelinization is in its incipient phase, as revealed by Luxol-Fast Blue staining (A), and there is a significant change in the MRIproperties of the cerebral wall (B and D): while contrast resolution of T1-weighted images (B) decreases, for the first time, it increases in T2-weighted images(C). Note that the main frontal crossroads area (asterisks) still displays characteristic histological and MRI features. Double arrowheads point to the externalcapsule.

4.4. Organization of fiber systems

During this period, the major events are the developmentand elaboration of the corona radiata, and all major segmentsof the cerebral white matter[1] can be recognized. SegmentI includes the corpus callosum, segment II represents thepeduncular part of the corona radiata, and segment III (cen-trum semiovale) becomes well-defined. Segment IV (gyralwhite matter) is present, but not yet fully developed, becausethe diminishing subplate zone remains interposed betweenthe corona radiata and the cortex. MRI features (i.e., lowMRI signal intensity on T1-weighted images) of the periven-

tricular crossroads (Fig. 8B, asterisk) and the ventricular partof the corpus callosum suggest that fibers continue to growin these regions.

5. Late fetuses and near-term preterm infants

Previously described maturational changes, as revealedby MR images, continue in late fetuses and preterm infants.However, during this period, T2-weighted images (Fig. 9C),for the first time, display certain cerebral structures (e.g.,basal ganglia) with better contrast resolution than T1-


weighted images (Fig. 9B). Whereas, the capsula internabecomes well-delineated due to the onset of myelinization,the border between the cortex and the subcortical white matterbecomes poorly delineated, despite the fact that the subplatezone has mostly disappeared and segment IV of the whitematter is now fully established. The ventricular zone is alsovery thin and has almost completely disappeared.

6. Conclusions

The correlation of in vitro MRI and histological analy-sis reveals that, in the developing human cerebrum, transientfetal zones can already be visualized on T1-weighted MRimages at 10 POW. The proliferative ventricular zone dis-plays a characteristically high MRI signal intensity due to thehigh cell-packing density of mitotic cells and postmigratoryneurons, respectively. Further characteristic MRI features ofthe early fetal cerebrum include the differentiation of limbicregions (hippocampus and entorhinal cortex) and the basalganglia. In the mid-fetal period, the cerebral wall displays atypical fetal lamination[1,2,4,5,7]. The salient feature of themid-fetal cerebrum is the transient subplate zone, which dis-plays a characteristic low MRI signal intensity[1,2], containsan abundant and hydrophyllic extracellular matrix, and servesas a “waiting” compartment for major classes of growingc bero RIs pri-m pusa ingp talh thati thep ni t andh RIv ity.I thatc

lam-i um.W sub-p nally,t ovedw lateg revi-o gs

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fully acknowledge the assistance of Zdenka Cmuk, DanicaBudinscak and Bozica Popovic for the preparation of histo-logical sections, and Pero Hrabac for the preparation of theillustrations.

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rmalm J

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logy

[ rds E.pre-

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[ ing.

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ortical afferents[1,16,21]. We also demonstrated a numf transient features that went unnoticed in previous Mtudies: the early differentiation of the entorhinal andary visual cortex; the modular organization of the cormygdaloideum; the periventricular crossroads of growathways[15]. In addition, we demonstrated that the feippocampal formation can be clearly delineated and

ts MRI appearance is different from that described inostnatal brain[25]. Namely, fetal hippocampal formatio

s characterized by a marginal zone with an abundanydrophyllic extracellular matrix, which enables its Misualization as a thin stripe of low MRI signal intensndeed, this is the only portion of the fetal marginal zonean be visualized by MRI.

After 26 POW, there are dramatic changes in thenar organization and MRI features of the fetal cerebr

e explain these changes by gradual dissolution of thelate zone and the development of the corona radiata. Fi

he observed changes in MRI features, as well as imprhite matter visualization on T2-weighted images duringestation, are in accordance with findings described in pus conventional MRI[1,4,5,8]and diffusion tensor imagintudies[2,12].

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This work has been supported by the Croatian Mstry of Science, Education and Sport grants to I.K. (go. 0108118) and M.J. (grant no. 0108115). We gr

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In vitro MRI of brain development

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