Developmental reorganization of the human cerebral cortex

1. Paediatr Croat 2007; 51 (Supl 1): 93-98 Pregled
Review
DEVELOPMENTAL REORGANIZATION OF THE HUMAN CEREBRAL CORTEX
IVICA KOSTOVIĆ1, ZDRAVKO PETANJEK1, 2
This paper reveals data on developmental reorganization of the human cortex. Three criteria were used to determine reorga-
nization: (1) presence of transient cellular zones: ventricular (VZ), subventricular (SVZ), intermediate (IZ) zone, subplate (SP),
cortical plate (CP) and marginal zone (MZ); (2) intensity of specific neurodevelopmental cellular events: proliferation, migration,
differentiation, growth of axon and synaptogenesis; (3) pattern of functional organization: (a) endogenous, transient circuitry and
(b) permanent, sensory driven circuitry. First half of gestation is characterized by proliferation and migration. During the second
half of gestation major axonal pathways grow through the intermediate zone and "wait" in the subplate. Initial synaptogenesis
begins during third month of gestation and is related to the endogenous, spontaneous circuitry. In early preterm thalamocortical
fibers relocate from the subplate (after 24th postconceptional weeks) and first evoked potentials may be recorded. The fundamental
pattern is coexistence of endogenous and permanent, sensory driven circuitry. In neonatal brain synaptogenesis is main neuroge-
netic event and there is gradual disappearance of transient endogenous circuitry and transient cellular zones. The review support
ideas of developmental "windows", selective vulnerability of specific transient cellular zones (subplate) and increased vulnerability
of the human fetal and neonatal brain.
Descriptors: PREMATURUS, KORTIKALNE VEZE, TALAMOKORTIKALNA VLAKNA, SINAPTOGENEZA, HISTOGENEZA
Acknowledgements: This work was ● presence of transient circuitry and ● Functional patterns in developing
supported by grants 108-1081870-1876 transient functions (1). brain might be (a) endogenous (spon-
(I.K.) and 108-1081870-1932 (Z.P.) from taneous), transient circuitry, mostly
the Croatian Ministry of Science, Educa- In this review we will discuss reor- characterized with oscillatory prop-
tion & Sport. ganization of developing brain based on erties and (b) sensory driven, perma-
these three basic patterns of organiza- nent circuitry (2, 3).
Introduction tion. Our focus will be on fetal, early pre-
term, late preterm and neonatal period. Transient patterns and their reorganization during
Fetal cortex differs from the neona-
In order to describe each of this periods prenatal and perinatal developmental "windows"
tal in three different aspects of organiza-
of development it is necessarily to define
tion:
transient zones, neurogenetic events and
Fetal period
● presence of transient cell zones in types of transient functional patterns.
which cellular events takes place; Fetal period is dominated by two
● Transient zones (Figure 1) in which
neurodevelopment events, proliferation
● intensity of specific neurodevelop- neurodevelopmental events take
and migration (4, 5). It is also a period
mental cellular events; places are ventricular zone (VZ),
when synaptogenesis begins and axonal
subventricular zone (SVZ), interme-
pathways (projections) establish. Prolif-
1
Department of Neuroscience diate zone (IZ), subplate (SP), cor-
Croatian Institute for Brain Research eration: Neurons are generated in ven-
tical plate (CP) and marginal zone
School of Medicine, University of Zagreb tricular and subventricular zone from
(MZ).
2
Department of Anatomy the neuronal stem cells by asymmetric
School of Medicine, University of Zagreb and symmetric divisions. The period of
● The neurodevelopmental cellular
Address: events which will be considered in proliferation of neurons is between 4th
Zdravko Petanjek, MD, PhD, Professor of this review are proliferation, migra- and 28th postconceptional week (Rakic
Anatomy & Neuroscience 2006, Cerebral Cortex). According to re-
Department of Neuroscience
tion and differentiation of neurons,
Croatian Institute for Brain Research axonal growth and synaptogenesis. cent evidence radial glia cells also serve
School of Medicine, University of Zagreb Myelinization and cell death will be as neural stem cell and might produce
10000 Zagreb, Šalata 12, Croatia not discussed in this review. pyramidal neurons (Rakic 2006). The
E-mail: zpetanjek@net.hr GABA-ergic (inhibitory interneurons) in
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2. I. Kostović et al. Developmental reorganization... Paediatr Croat 2007; 51 (Supl 1): 93-98
Migration: Newly generated neu- Pattern of functional organization:
rons migrate along radial glia cells In the fetal cortex there is no sensory
through intermediate zone and form em- driven activity. However, synapse seems
bryonic column (4). The disturbances of to be very active (3). This type of oscilla-
proliferation and migration might result tory activity was described as spontane-
in so called migratory disorders, which ous activity (2, 3, 5, 17). Early thalamic
are frequently associated with epilepsy input to subplate might participate in this
and mental retardation. Transient lami- circuitry, as a transient input. Subplate
nar pattern: After 13 postconceptional neurons have also efferent projection to
week a new lamina develops below cor- thalamus and subcortical centers and
tical plate and became very soon thickest this presumably glutamatergic output
lamina of the telencephalon. This lamina might contribute to generation of fetal
is subplate zone which can be seen on general movements (18). In conclusion,
both Nissl preparations and magnetic early fetal circuitry is transient and it is
resonance images in vivo and in vitro (6, related to transient pattern of structural
7). Prominent subplate zone is the main organization. This concept is accepted
characteristic of fetal pattern of laminar by most modern neurophysiologist and it
organization. It is easy to distinguish the is in contrast with some classical opin-
following layers (from ventricle to pia): ions about reflex type generation of fetal
VZ, SVZ, IZ, SP, CP and MZ (Figure 1). motility.
The subplate zone is site of early syn-
aptogenesis, endogenous neural activity Early preterm period
and neuronal differentiation.
Figure 1 During early preterm period several
Transient laminar organization of the Growth of axonal pathways: The reorganizational events take place. This
telencephalic wall:
Cresyl violet (Nissl) staining of the earliest pathways which arrive in fe- period is characterized by development
telencephalic wall in the human fetus during tal cortex are monoaminergic afferents of primary gyri and sulci (19-21). Tran-
midgestation; transient zones in which from brain stem tegmentum and cholin- sient laminar organization: For the first
neurodevelopmental events take place are ergic afferents from the basal nucleus time there is initial lamination in corti-
ventricular zone (VZ), subventricular zone
(SVZ), intermediate zone (IZ), subplate (SP), of Maynert (8-10). Next afferents in se- cal plate, which coexists with extremely
cortical plate (CP) and marginal zone (MZ) quentional growth are massive pathways prominent subplate zone. This is a spe-
Slika 1. originating in thalamus. Thalamic fibers cial feature of preterm cortex and mix-
Prolazna laminarna organizacija stjenke originate not only from sensory tha- ture of fetal and permanent patterns (2,
telencefalona: lamic nuclei, but also from associative 14). Neurogenetic events: Intensity of
Krezil violet (Nisslovo) bojanje stjenke proliferation and migration during pre-
thalamic nuclei (2, 5, 11-13). This most
telencefalona u fetusa čovjeka tijekom srednje
trećine trudnoće: prolazni stanični slojevi koji massive input grows throughout subplate term period decreased significantly. Ven-
su mjesto specifičnih neurorazvojnih događaja zone during prolonged period of axonal tricular zone become thinner and neural
su: ventrikularni (VZ), subventrikularni pathfinding (14). At the end of fetal pe- stem cells gradually stop producing neu-
(SVZ), intermedijarni (IZ) sloj (zona), sloj rons and continue to produce glia cell
riod that is between 21-23 postconcep-
ispod ploče (subplate-SP), kortikalna ploča
(CP) i marginalni sloj (zona) (MZ) tional weeks, thalamocortical afferents lines (proolygodendrocites, astrocytes).
accumulate in the superficial part of the Migration decreases in intensity and late
subplate zone (5, 13). These fibers are de- born neurons only might be found to mi-
humans originate in the pallial (cortical)
scribed as "waiting" fibers. grate through intermediate zone.
ventricular zone, while in rodent brain
main source of GABA-ergic neurons is Synaptogenesis: Early synapses de- Axonal growth: The crucial event in
in another germinal structure called gan- velop above and below cortical plate. axonal growth is relocation of thalamic
glionic eminence. Several distinct fea- Below cortical plate is plexiform pre- afferents from subplate zone and their
tures distinguish human brain from other subplate layer and above cortical plate is ingrowth into cortical plate. That event
species, especially rodents (4). This is on marginal zone. This early fetal pattern of occurs almost simultaneously in primary
the first place increased number of mitot- synaptic distribution might be described and associative cortex (11-13). Parallel to
ic cycles (35 in human compared to 11 in as period of two synaptic strata (15, 16). the thalamo-cortical ingrowth there is
the rodents). Second, there is local gen- The early postsynaptic elements are pre- rapid areal differentiation (14, 22). Syn-
eration of the GABA-ergic interneurons plate and marginal zone neurons, as well aptogenesis: In the early preterm infant
(as stated above). Third, ganglionic emi- as branches of cortical plate neurons synapses are formed, for the first time,
nence which is the basal enlargement of which are distributed in marginal zone within deep part of the cortical plate (15,
the basal telencephalic ventricular zone and preplate (15). 16). This intracortical synaptogenesis is
generates also neurons for thalamus (4). related to development of thalamo-corti-
cal circuitry (12-14).
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3. I. Kostović et al. Developmental reorganization... Paediatr Croat 2007; 51 (Supl 1): 93-98
Functional pattern of organization: still waiting in subplate, and majority as it was show by Burkhalter et al. (42).
Development of thalamocortical connec- of "permanent" axons are already in the Functional pattern: The main character-
tivity explains early evoked potential in cortical plate. istic of neonatal period is establishment
preterm infant (23-27). The early devel- of sensory driven activity. This is par-
opment of evoked potential in preterm Synaptogenesis and neuronal differ- ticularly important for development of
infant together with transient circuitry in entiation: Synaptogenesis is proceeding columnar organization in sensory corti-
subplate shows that there are interactions very fast in superficial part of cortical ces (3). Also, there is synchronization in
between endogenous circuitry of the sub- plate paralleled with accelerated devel- EEG and sleep pattern, transient general
plate zone, and thalamic sensory driven opment of dendrites pyramidal neurons movements still persist in the neonatal
circuitry (2, 3). Same thalamic terminals (35, 36). Functional pattern: Due to the period indicating immaturity of cortical
might activate cell in the cortical plate fast synaptogenesis in superficial cortex, and subcortical circuitry (18).
and form synapses in subplate. This co- cortical electrical dipole changes and
existence with transient endogens and surface negative response dominates in
electrical recordings. There is gradual Discussion
permanent driven circuitry might exist
in the human preterm for a prolonged disappearance of giant potentials and
In this review we have presented
time (2). This combined circuitry seems synchronization of EEG (23, 37).
evidence that fetal and preterm cortex
to be essential feature of the preterm in- shows transient pattern of organiza-
fant and underlie transient electrophysi- Neonatal period tion and permanent developmental re-
ological and behavioral phenomena (23, organization. These phenomena were
28-30). Establishment of thalamo-corti- During neonatal period fetal and also observed using different structural
cal connection with somatosensory cor- preterm patterns are reorganized dra- approaches and physiological record-
tex attracted recently a great attention matically. This reorganization from tran- ings (1, 4). Neurodevelopmental cellu-
among anesthesiologists, due to the fact sitional patterns to final organization is lar event occur with different intensity
that this pathway may represent anatom- crucial for understanding physiological throughout development. The periods of
ical substrate for pain input to cortex in and behavioral phenomena in neonatal increased cellular activity might also be
early preterm infants (7, 14, 16, 31, 32). period. Laminar organization: Neocor- described as developmental "windows".
The final prove that pain stimuli can tex develops into typical six layered pat- Throughout each developmental window
reach human cortex in early preterm in- tern. However, layer IV (granular layer) transient zones display characteristic
fants comes from study of M. Fitcgerald is still present in motor cortex (in adult structural and chemical properties. In
showing changes in cortical blood flow motor cortex is agranular) (14). Second, our review we have emphasized out that
detected by infrared monitoring after subplate zone is not different cytoarchi- transient zones are essential spatial pa-
pain peripheral stimuli (33). tectonic layer due to the full development rameters for cellular events (4, 6). Using
of white matter in cortical gyri. Howev- imaging techniques it is possible to visu-
er, subplate neurons remain as the inter- alize all transient cellular zones (7). Ex-
Late preterm face between layer VI and white matter. ception is marginal zone which is visible
Transient laminar pattern: In the In the associative cortex neurons of the in the hippocampal cortex only, while in
late preterm transient laminar pattern subplate might exist as a distinct popula- neocortical areas is beyond resolution of
gradually disappear and six layer Brod- tion as long as 6 months (38). Some of 1.5 T imaging.
mann grundtypus appeared (1, 14). De- the cells die by naturally occurring cell
velopmental events: There is no produc- death (4, 15). The demonstration of transient cel-
tion of neurons, except in hippocampal lular zones is important for in-vivo as-
Neurogenetic events: Two neuro- sessment of structural and functional
cellular formation and olfactory region. genetic events dominate early postna-
All neurons are in final position and mi- development and reorganization of the
tal development. First this is explosive human fetal and preterm brain (5). In ad-
gratory processes stopped. Radial glial development of synapses and second
cells which were main guides for radial dition, magnetic resonance imaging of
is the extensive production of postsyn- transient patterns of organization is im-
migratory neurons undergone transfor- aptic spines (39, 40). Axons: The major
mation in atrocities (4). Axonal growth: portant for contemporary diagnostic pro-
reorganization during neonatal period cedures (20, 21, 43-45). We believe that
Callosal fibers show overgrowth phe- is related to exuberant callosal axons.
nomena (exuberance) and the number of abnormalities of transient cellular zones
The newborn monkey shows three times might be objectively analyzed in differ-
axons in corpus callosum is higher then grater number of axons than adult mon-
in adult brain. The overgrowth of corpus ent genetic and epigenetic pathologies.
key (34). The same phenomena have The knowledge about reorganization of
callosum was proven by counting axons been described in the human brain (41).
on the midsagital sections (34). Within developing cortex is of great significance
However, the exact time of axon reduc- of our understanding of structural plas-
the hemisphere there are three major tion in man is not known, but is expected
patterns of callosal distribution. Some ticity and vulnerability of the human
to occur during early postnatal time (41). brain. For example, thalamocortical af-
axons are distributed within the white During neonatal period there is continua-
matter around ventricles, other axons are ferents are in "waiting" position in the
tion of short corticocortical fiber growth
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4. I. Kostović et al. Developmental reorganization... Paediatr Croat 2007; 51 (Supl 1): 93-98
poxia-ischemia (44, 49). It was proposed growing axons and subplate zone, pos-
that subplate neural elements might be sibilities of neuroprotection and their vi-
partially involved in diffuse periven- sualization with modern magnetic reso-
tricular "lesion", so called DEHSI (5, 44, nance imaging techniques, is the most
48, 50). It was found using diffusion ten- challenging task in modern developmen-
sor imaging that DEHSI is the most fre- tal neurology. The role of transient neu-
quent finding in preterm infants (51-53). ronal circuitry and plasticity opens new
Searching for structural correlates and visitas for the treatment of the children
pathogenesis of this important MR find- with perinatal brain injury.
ing remains the most challenging task in
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Sažetak
RAZVOJNA REORGANIZACIJA KORE MOZGA ČOVJEKA
I. Kostović, Z. Petanjek
U ovom preglednom članku osvrnuli smo se na razvojnu reorganizaciju ljudskog mozga. Tri kriterija korištena su u svrhu
određivanja reorganizacije: (1) prisutnost prolaznih staničnih slojeva: ventrikularni (VZ), subventrikularni (SVZ), intermedijarni
(IZ) sloj (zona), sloj ispod ploče (subplate-SP), kortikalna ploča (CP) i marginalni sloj (zona) (MZ); (2) intenzitet specifičnih neu-
rorazvojnih staničnih događaja: proliferacija, migracija, diferencijacija, izrastanje aksona i sinaptogeneza; (3) obrazac unutarnje
funkcionalne organizacije: (a) prolazni, endogeni neuralni krugovi, te (b) trajni, osjetno stimulirani neuralni krugovi. Prva polovi-
ca trudnoće obilježena je proliferacijom i migracijom. Tijekom druge polovice trudnoće glavni aksonski putovi urastaju kroz inter-
medijarni sloj i "čekaju" u sloju pod pločom. Prve sinapse vidljive su tijekom trećeg mjeseca trudnoće i povezane su s unutarnjim,
spontanim neuralnim krugovima. U ranog prematurusa (nakon 24. postkoncepcijskog tjedna) talamokortikalna vlakna premještaju
se iz sloja pod pločom i urastaju u kortikalnu ploču, te se mogu po prvi puta zapaziti evocirani potencijali. Osnovno obilježje je
istodobna prisutnost unutarnjih i trajnih, osjetno stimuliranih neuralnih krugova. U mozgu novorođenčeta sinaptogeneza je glavno
neurorazvojno događanje, a također dolazi i do postupnog nestanka prolaznih unutarnjih neuralnih krugova i prolaznih staničnih
slojeva. Ovaj pregledni rad podupire hipotezu o razvojnim "prozorima", selektivnoj vulnerabilnosti i specifičnim, prolaznim fetal-
nim slojevima (subplate), te povećanoj vulnerabilnosti mozga fetusa i novorođenčeta čovjeka.
Deskriptori: PRETERM INFANT, CEREBRAL PATHWAYS, THALAMOCORTICAL AFFERENTS, SYNAPTOGENESIS, HISTOGENESIS
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