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Journal of Maternal-Fetal and Neonatal Medicine, 2012; Early Online: 1–3© 2012 Informa UK, Ltd.ISSN 1476-7058 print/ISSN 1476-4954 onlineDOI: 10.3109/14767058.2012.664351

The term “viability” is not simply a synonymous with being “born alive,” but is closely related to the capability of having a “meaningful life” and having a reasonable period of survival. The definition of “viability” is generally based on two major criteria: the biological, which takes into consideration the maturity of the foetus, and the epidemiological, which is based on the survival rates reported in literature. The neuromaturation of the cerebral cortex is a dynamic process promoted by the subplate, a transient population of neurons that guides the development of cortical and thalamocortical connections. These connections are for example fundamental for cortical processing of sensory information and mental processes. The first thalamocortical and cortico-cortical connections grows at 23–24 postconceptional weeks, which coincides with the age limit for premature baby survival.

Keywords: birth, CNS, GABA, light, SATs, subplate zone

Abbreviations: CNS, central nervous system; GABA, aminobutyric acid; PCW, postconceptional week; SATs, spontaneous activity transients

IntroductionOver the last 50 years, the rising preterm birth rate, the progres-sive decrease in preterm mortality and lowering of the limit of viability have made preterm birth a significant public health problem [1–7]. Neuromaturation, the functional development of the central nervous system (CNS), is a dynamic process that promotes and shapes CNS structural development.

Maturation of cerebral connectionsThe term “viability” is not simply a synonymous with being “born alive,” but this closely related to the concepts of capability of “meaningful life” and of reasonable period of survival. The definition of “viability” is generally based on two major criteria: the biological, which takes into consideration the maturity of the foetus, and the epidemiological, which is based on the survival rates reported in literature 8. The CNS appears at the beginning of the 3rd postconceptional week (PCW) as an ectodermic thick-ening, the neural plate. Its lateral margins are raised to form the neural folds. With the further development, margins continue to rise and move closer to the midline and finally merge, giving rise to the neural tube. The fusion begins in the cervical region and

proceeds toward the end of cerebro-cranial to the caudal embryo. The final closure of the cranial neuroporo occurs at 25th day of postconceptional age; the closure of the caudal neuroporo occurs about 2 days later. The basic divisions of the adult brain start from the 6th PCW. All neurons that populate the cortex originate from periventricular subependymal zone through the processes of cells proliferation, migration and differentiation. The migration takes place according to rhythmic waves from 8th PCW to 24th PCW. The skin originates from the same sheet as all ectodermal struc-tures of the CNS. The skin’s receptors appear very early around the 8th PCW. They extend their axons from the paravertebral ganglia to thalamus around the 18th–20th PCW. Observation of the human fetus have shown that the first discernible movements are detectable from 7th to 8th PCW. The embryonic and fetal movements are automatic motor patterns (self-generated) and originate from the spinal cord under the control of the brainstem. Movements have maximum expression around 15th PCW. These spontaneous movements provide a rich source of somatosensory information that affects the wiring of the participating neuronal networks. The source of the movements is “endogenous” [9]. They stimulate muscle, tendon and skin receptors and allow the forma-tion of connections from the periphery to the spinal centers. The subsequent connections with thalamus are related to stimulation of cutaneous receptors [10]. Oligohydramnios leads to a reduc-tion of fetal movements and possibly to poor sensory stimulation Rudimentary cortical evoked responses to somatosensory stimu-lation can be recorded at 24 PCW, reflecting the commencing ingrowth of thalamocortical axons in the somatosensory cortex. By 29th PCW, a more mature response has developed [11].

Subplate zoneThe subplate zone is a transient cytoarchitectonic compartment of the foetal telencephalic wall and contains a population of neurons which are the main neurons of the foetal neocortex and play a key role in normal development of cerebral cortical structure and connectivity. In particular, the subplate is a guide for cortical- and thalamus-cortical connections which are essential in order to connect the center to the periphery. It serves as a waiting compartment for growing cortical afferents; its cells are involved in the establishment of pioneering cortical efferent projections and transient fetal circuitry. The subplate zone is a phylogeneti-cally recent structure and it is mostly developed in the human brain. Histologically, the subplate is composed of numerous cells (neurons, glia, endothelial cells of blood vessels), surrounded by

REVIEW ARTICLE

Functional maturation of neocortex: a base of viabilityM. G. Gatti2, E. Becucci1, F. Fargnoli3, Massimo Fagioli4, U. Ådén5 & G. Buonocore1,2

1Department of Pediatric, Obstetric and Reproductive Medicine, University of Siena, Siena, Italy, 2Neonatal follow up and Neurodevelopment Outcome Unit, Department of Pediatric, Obstetric and Reproductive Medicine, University of Siena, Siena, Italy, 3Department of Neurosciences, Psychiatry Unit, University of Siena, Siena, Italy, 4Department of Philosophy, Humanities and Education, University of Chieti, Chieti, Italy, and 5Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm Sweden

Correspondence: M.G. Gatti, Department of Pediatric, Obstetric and Reproductive Medicine. Tel: 338 1584122. E-mail: m.g.gatti@hotmail.it

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2 M. G. Gatti et al.

Journal of Maternal-Fetal and Neonatal Medicine

an abundance of highly hydrophilic extracellular matrix, rich in glycosaminoglycans, chondroitin aminoglycans, laminin, fibronectin and adhesion molecules [12]. The functional matura-tion of the subplate zone at 23th–24th PCW corresponds to the age currently considered the lowest limit for survival of prema-ture infants [13]. In the subplate, different densities of innervation can be observed in separate compartments at particular stages of development. There is a massive accumulation of thalamocortical fibres and synapses in the superficial compartment at 21–23th PCW just prior to the end of the waiting period and invasion of the cortical plate. This event is visible by in utero imaging [13,14]. During the second trimester, the subplate increases significantly in thickness and complexity. The subplate zone plays also a role in the mechanisms underlying spontaneous activity transients (SATs). The SATs are characterized by very low frequency waves with higher frequency components superimposed. They corre-spond to intermitted periods with delta activity, as recorded by Electroencephalography (EEG) and could be present as early as at 23–24th PCW [13]. SATs represent a family of network events characteristic of immature brain circuitries. SATs events are trigged by endogenous mechanism in the subplate [13]. Some in utero studies have shown that SATs events can be trigged even by somatosensory stimuli demonstrating that exogenous stimuli generate an electrical endogenous response. Thus, in the foetus, there is no difference between endogenous and evoked stimuli in terms of electrical response. This confirms that stimuli are not finalized to transmit information but to structure and organize subplate-thalamic-cortical connections. Around 30th PCW, a significant proportion of SATs become roughly coinci-dent between hemispheres. A more precise and more consistent temporal synchrony of SATs arise only later, starting at around 35th PCW, paralleling the appearance of interemispheric connec-tions [13,14]. Subplate neurons play an important role in thal-amocortical axon path finding at the level of the initial areal targeting as well as the eventual innervations of cortical layer IV by thalamic afferents and establishment of optical orienta-tion columns [15,16]. Two neurons phenotypes class exist in the subplate: glutamatergic acid neurons and gamma-aminobutyric acid (GABA) neurons; each class express heterogeneous molec-ular markers [17]. It is not yet clear whether the same types of subplate neurons possess intracortical and extracortical projec-tions and how the diverse somatodendritic morphologies relate to the equally diverse neurochemical properties and physiological fingerprints [18]. In humans, the subplate zone becomes visible as a cell-poor fibre-rich layer situated between the intermediate zone and cortical plate at the beginning of the second trimester (14–15th PCW) of gestation [19]. Presubplate zone begins from the deepest layer of the cortical plate that contains few neurons but a differentiated neuropil featuring dendritic arborisations and synapses, including GABAergic elements and monoaminergic innervation from the brainstem [20].

Subplate and birthAt birth, the newborn brain has an almost adult number of neurons but an immature set of connections [13].The foetus’s cerebral “status” is characterized by the SATs. They represent characteristic events of foetal brain circuitries. SATs are trigged by endogenous mechanisms due to different role of neurons and neurotransmitters in foetal brain, that have the function of organizing and structuring the neuronal networks. The delivery from the mother’s womb causes a passage between “foetal-status” to “newborn-status”. The arousal of the newborn can probably partially be due to the activation of the noradrenergic system in

the brain, particularly locus coeruleus from where noradrenergic neurons are distributed in the whole brain. The catecholamine surge, triggered by vaginal delivery, may also be critical for the arousal at birth [21,22]. GABA plays a key role in the transition passage from foetal to neonatal life. The subplate induce a neurons differentiation in monoaminerigic, GABAergic and glutamatergic line. In fact, the neurochemistry of the foetal brain reveals that GABA is the dominant excitatory neurotransmitter during fetal life with the function of develop cerebral cortical structure and connectivity [10,23]. Soon before or around birth depending on the brain area, GABA becomes the main inhibitory neurotrans-mitter changing completely the cerebral electrical activity. This is a consequence of the expression of the K/Cl cotransporter KCC2 that creates a low intracellular Cl concentration [24]. The switch in GABA signaling from foetal excitatory to inhibitory function is elicited by light retinal stimulation, through the upregulation of KCC2 cotransporter [25].

The switch in GABA function permitted the passage between foetal-status to newborn-status. These physiological findings strongly support the theory of Fagioli, psychiatrist who first theorized that the light retinal stimulation generates, at birth, the arousal of cerebral cortex and the beginning of human thought [26].

Conclusion“Capacity to react” to sensory stimuli is a fundamental aspect of the viability of the preterm and full-term newborn. At 23–24th weeks, the presence of neural connections between the sense organs and the cortex makes it possible for the fetus to react to a sensory stimulus. The viability starts with the formation of thal-amocortical connections to zone at 23–24th PCW. The subplate represents the earliest connection between peripheral receptors, thalamus and cortex. At birth, there is a rapid transition from endogenous to stimulus driven activity. This coincides with the altered function of the neurotransmitter GABA from excitatory to inhibitory.

Declaration of interest: Research support was provided by grants from the Fondazione Mariani, Milan, Italy – GRANT “R-10–81” – and Fondazione EURAIBI Onlus, Department of Pediatrics, Obstetrics and Reproductive Medicine, Policlinico Le Scotte, University of Siena, Siena, Italy. The content of this supplement has been externally peer-reviewed by the International Scientific Board of EURAIBI. The content has not undergone further addi-tional external peer-review by the journal, but has been editorially screened and approved by the Editors-in-Chief.

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