A lateral-to-mesial organization of human ventral visual cortex at birth.

In human adults, ventral extra-striate visual cortex contains a mosaic of functionally specialized areas, some responding preferentially to natural visual categories such as faces (fusiform face area) or places (parahippocampal place area) and others to cultural inventions such as written words and numbers (visual word form and number form areas). It has been hypothesized that this mosaic arises from innate biases in cortico-cortical connectivity. We tested this hypothesis by examining functional resting-state correlation at birth using fMRI data from full-term human newborns. The results revealed that ventral visual regions are functionally connected with their contra-lateral homologous regions and also exhibit distinct patterns of long-distance functional correlation with anterior associative regions. A mesial-to-lateral organization was observed, with the signal of the more lateral regions, including the sites of visual word and number form areas, exhibiting higher correlations with voxels of the prefrontal, inferior parietal and temporal cortices, including language areas. Finally, we observed hemispheric asymmetries in the functional correlation of key areas of the language network that may influence later adult hemispheric lateralization. We suggest that long-distance circuits present at birth constrain the subsequent functional differentiation of the ventral visual cortex.

Cranial ultrasound and MRI at term age in extremely preterm infants.

OBJECTIVES: Conventional MRI at term age has been reported to be superior to cranial ultrasound (cUS) in detecting white matter (WM) abnormalities and predicting outcome in preterm infants. However, in a previous study cUS was performed during the first 6 weeks only and not in parallel to MRI at term age. Therefore, the aim of the present work was to study brain injuries in preterm infants performing concomitant cUS and MRI at full-term age. METHODS: In a population-based cohort of 72 extremely low gestational age infants paired cUS and conventional MRI were performed at term age. Abnormalities on MRI were graded according to a previously published scoring system. On cUS images the lateral ventricles, the corpus callosum, the interhemispheric fissure and the subarachnoidal spaces were measured and the presence of cysts, grey matter abnormalities and gyral folding were scored. RESULTS: Moderate or severe WM abnormalities were detected on MRI in 17% of infants and abnormalities of the grey matter in 11% of infants. Among infants with normal ultrasound (n=28, 39%) none had moderate or severe WM abnormalities or abnormal grey matter on MRI. All infants with severe abnormalities (n=3, 4%) were identified as severe on MRI and cUS. CONCLUSIONS: All severe WM abnormalities identified on MRI at term age were also detected by cUS at term, providing the examinations were performed on the same day. Infants with normal cUS at term age were found to have a normal MRI or only mild WM abnormalities on MRI at term age.

Therapeutic hypothermia can be induced and maintained using either commercial water bottles or a "phase changing material" mattress in a newborn piglet model.

BACKGROUND: Therapeutic hypothermia, a safe and effective treatment for neonatal encephalopathy in an intensive care setting, is not available in low-resource settings. Aims/ METHODS: To assess two low-tech, low-cost cooling devices for use in low-resource settings: (i) commercially available water bottles filled with tepid water (25 degrees C); (ii) a mattress made of phase changing material (PCM) with a melting point of 32 degrees C (PCM works as a heat buffer at this temperature). Eleven anaesthetised newborn piglets were studied following transient hypoxia-ischaemia. The cooling device was applied 2-26 h after hypoxia-ischaemia with a target rectal temperature (T(rectal)) of 33-34 degrees C. T(rectal) undershoot was adjusted using cotton blankets; the cooling device was renewed when T(rectal) rose above 35 degrees C. T(rectal) data during cooling were dichotomised (within or without target) to assess: (a) the total period within the target T(rectal) range; (b) the stability and fluctuation of T(rectal) during cooling. RESULTS: Therapeutic hypothermia was achieved with both water bottles (n = 5) and the PCM mattress (n = 6). The mean (SD) time to reach target T(rectal) was 1.8 (0.5) h with water bottles and 1.9 (0.3) h with PCM. PCM cooling led to a longer period within the target T(rectal) range (p<0.01) and more stable cooling (p<0.05). Water bottle cooling required device renewal (in four out of five piglets). CONCLUSION: Simple, low-tech cooling devices can induce and maintain therapeutic hypothermia effectively in a porcine model of neonatal encephalopathy, although frequent fine tuning by adjusting the number of blankets insulating the piglet was required to maintain a stable temperature. PCM may induce more stable cooling compared with water bottles.

Mode of delivery modulates physiological and behavioral responses to neonatal pain.

OBJECTIVE: To study whether the mode of delivery alters pain expression. STUDY DESIGN: Full-term infants born by vaginal delivery or elective caesarean section were observed following high- and low-intensity pain stimuli, with recording of electrocardiogram, facial expression and vocalization. RESULT: Graded physiological and behavioral responses occurred, with greater responses to higher than lower intensity pain stimuli. Elevation in heart rate following both stimuli increased with time after vaginal delivery. Infants delivered by elective caesarean section showed stronger facial expressions and briefer time in vocalizations response to both interventions. CONCLUSION: Diminished responses following vaginal delivery suggest that physiological events associated with a normal delivery reduce the physiologic and sympathoadrenal activation by nociceptive mechanisms. Pain and stress reactivity appear to be inhibited during fetal life and sensory inputs during vaginal delivery may reverse this inhibition. To minimize neonatal pain, we recommend that postnatal invasive procedures to be performed shortly after vaginal birth.

Altered respiratory pattern and hypoxic response in transgenic newborn mice lacking the tachykinin-1 gene.

Substance P is known to be involved in respiratory rhythm and central pattern-generating mechanisms, especially during early development. We therefore studied respiratory responses in transgenic newborn mice (Tac1(-/-)) lacking substance P and neurokinin A (NKA). In vivo, the effects of intermittent isocapnic hypoxia (IH) and hypercapnia were studied using whole body flow plethysmography at P2-3 and P8-10. In vitro, anoxic responses and the effects of hypocapnic and hypercapnic conditions were studied in brain stem-spinal cord preparations (C4 activity) at P2. Hypoxic challenge considerably modified the respiratory activity in transgenic mice displayed in vivo as an attenuated increase in tidal volume during IH. Transgenic mice also showed a more prominent posthypoxic frequency decline in vivo, and posthypoxic neuronal arrests appeared more often in vitro. We recognized two types of sigh activity: with or without a following pause. During IH, the amount of sighs with a pause decreased and those without increased, a redistribution that became stronger with age only in controls. Intermittent anoxia induced long-term facilitation effects in controls, but not in Tac1(-/-) animals, manifested as an increase in burst frequency in vitro and by an augmentation of ventilation during posthypoxic periods in vivo. Thus our data demonstrate that a functional substance P/NKA system is of great importance for the generation of an adequate respiratory response to hypoxic provocation in newborn mice and during early maturation. It also indicates that substance P (and/or NKA) is involved in the development of the plasticity of the respiratory system.

Increased catecholamines and heart rate in children with low birth weight: perinatal contributions to sympathoadrenal overactivity.

BACKGROUND: Low birth weight is associated with cardiovascular disease. The underlying mechanisms are unknown. We hypothesized that perinatal stress alters autonomic regulation of the cardiovascular system. In this study, catecholamines, heart rate (HR) and blood pressure (BP) were measured in healthy children with low birth weight. METHODS: This clinical study included 105 children (mean age 9.6 years) in three groups; born at term with normal birth weight (controls, n=37), born at term but small for gestational age (SGA, n=29) and born preterm (Preterm, n=39). Dopamine, adrenaline and noradrenaline were determined in urine. HR and BP were measured at rest, during an orthostatic test and after a mathematical mental stress test. RESULTS: Children in the Preterm and SGA groups excreted higher levels of catecholamines when compared with controls. HR (mean [SD] values) were higher at rest and after mental stress in Preterm (at rest 76 [9] and after mental stress 82 [12] min(-1)) and in SGA (79 [8] and 82 [10]) when compared with controls (70 [9] and 75 [9]). HR correlated with urinary catecholamines (r=0.24-0.27, P<0.05). Blood pressures measured at rest, during orthostatic testing and after mental stress did not differ between the groups. CONCLUSIONS: Preterm birth and fetal growth restriction are associated with increased sympathoadrenal activity in childhood, as indicated by stress-induced increases in HR and urinary catecholamines. These findings suggest that the cardiovascular control is differently programmed in these children with possibly higher risk of developing hypertension in adulthood.

Early postnatal changes in respiratory activity in rat in vitro and modulatory effects of substance P.

Developmental changes in the respiratory activity and its modulation by substance P (SP) were studied in the neonatal rat brainstem-spinal cord preparation from the day of birth to day 3 (P0-P3). The respiratory network activity in the ventrolateral medulla was represented by two types of bursts: basic regular bursts with typical decrementing shape and biphasic bursts appearing after augmented biphasic discharges in inspiratory neurons. With advancing postnatal age the respiratory output was considerably modified; the basic rhythm became faster by 20%, whereas the biphasic burst rate, which was originally 15 times slower, declined further by 180% and the C4 burst duration significantly decreased by 20% due to reduced decay time without preceding changes in the central inspiratory drive. SP had an age-dependent excitatory effect on respiratory activity. In the basic rhythm, SP could induce transient rhythm cessations on P0-P2 but not on P3. For the biphasic burst frequency, the sensitivity to SP significantly decreased from P0 to P3, whereas the range of SP-induced changes increased. In both types of bursts, SP prolonged C4 burst duration due to increasing decay time. This effect was three times greater on P3 and did not depend on the central inspiratory drive. Our results suggest that the potency of SP to regulate the respiratory activity elevates during the early postnatal period. The developmental changes in the respiratory activity appear to represent the transient stage in the maturation of rhythm and pattern generation mechanisms facilitating adaptive behavior of a quickly growing organism.

Control of breathing in newborn mice lacking the beta-2 nAChR subunit.

AIM: To study the ventilatory and arousal/defence responses to hypoxia in newborn mutant mice lacking the beta2 subunit of the nicotinic acetylcholine receptors. METHODS: Breathing variables were measured non-invasively in mutant (n = 31) and wild-type age-matched mice (n = 57) at 2 and 8 days of age using flow barometric whole-body plethysmography. The arousal/defence response to hypoxia was determined using behavioural criteria. RESULTS: On day 2, mutant pups had significantly greater baseline ventilation (16%) than wild-type pups (P < 0.02). Mutant pups had a decreased hypoxic ventilatory declines. Arousal latency was significantly shorter in mutant than in wild-type pups (133 +/- 40 vs. 146 +/- 20 s, respectively, P < 0.026). However, the duration of movement elicited by hypoxia was shorter in mutant than in wild-type pups (14.7 +/- 5.9 vs. 23.0 +/- 10.7 s, respectively, P < 0.0005). Most differences disappeared on P8, suggesting a high degree of functional plasticity. CONCLUSION: The blunted hypoxic ventilatory decline and the shorter arousal latency on day 2 suggested that disruption of the beta2 nicotinic acetylcholine receptors impaired inhibitory processes affecting both the ventilatory and the arousal response to hypoxia during postnatal development.

Preschool outcome in children born very prematurely and cared for according to the Newborn Individualized Developmental Care and Assessment Program (NIDCAP).

AIM: Care based on the Newborn Individualized Developmental Care and Assessment Program (NIDCAP) has been reported to exert a positive impact on the development of prematurely born infants. The aim of the present investigation was to determine the effect of such care on the development at preschool age of children born with a gestational age of less than 32 wk. METHODS: All surviving infants in a randomised controlled trial with infants born at a postmenstrual age less than 32 wk (11 in the NIDCAP group and 15 in the control group) were examined at 66.3 (6.0) mo corrected for prematurity [mean (SD)]. In the assessment we employed the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R) for cognition, Movement Assessment Battery for Children (Movement ABC) for motor function, subtests of the NEPSY test battery for attention and distractibility, and the WHO definitions of impairment, disability and handicap. Exact binary logistic regression was employed. RESULTS: There were no significant differences between the intervention group in Full-Scale IQ 93.4 (14.2) [mean (SD)] versus the control group 89.6 (27.2), Verbal IQ 93.6 (16.4) versus 93.7 (26.8) or Performance IQ 94.3 (14.7) versus 86.3 (24.8). In the NIDCAP group 8/13 (62%) survived without disability and for the children with conventional care this ratio was 7/19 (37%). The corresponding ratios for surviving without mental retardation were 10/13 (77%) and 11/19 (58%), and for surviving without attention deficits 10/13 (77%) and 10/19 (53%). Overall, the differences were not statistically significant, although the odds ratio for surviving with normal behaviour was statistical significant after correcting for group imbalances in gestational age, gender, growth retardation and educational level of the parents. CONCLUSION: Our trial suggests a positive impact by NIDCAP on behaviour at preschool age in a sample of infants born very prematurely. However, due to problems of recruitment less than half of the anticipated subjects were included in the study, which implies a low power and calls for caution in interpreting our findings. Larger trials in different cultural contexts are warranted.

Two types of rhythm in the respiratory network output in the isolated ventrolateral medulla in the neonatal rats.

Effects of substance P and extracellular [K(+)](o) on respiratory motor activity in the ventrolateral medulla in neonatal rat (0-4 days old) brainstem-spinal cord preparation were studied. In addition to fictive eupneic rhythm (8-13 bursts/minute), the respiratory motor output was composed of biphasic bursts which might underlie the sigh pattern in vivo. These bursts had considerably lower frequency (0.15-0.86 bursts/minute) and appeared when inspiratory neurons generated augmented biphasic discharges. The two rhythms were differently affected when the respiratory network excitability was increased by substance P or decreased by lowering external [K(+)](o), the effects on biphasic burst frequency being considerably greater. The augmented bursts could suppress inspiratory, but not pre-inspiratory neuron discharge, suggesting that pre-inspiratory neurons formed a supplementary rhythmic network which was not directly affected by biphasic burst generation.

Vitamin A and sudden infant death syndrome in Scandinavia 1992-1995.

AIM: To assess the effect of vitamin supplementation on the risk of sudden infant death syndrome (SIDS). METHODS: The analyses are based on data from the Nordic Epidemiological SIDS Study, a case-control study in which parents of SIDS victims in the Scandinavian countries were invited to participate together with parents of four matched controls between 1 September 1992 and 31 August 1995. The odds ratios presented are computed by conditional logistic regression analysis. RESULTS: The crude odds ratio in Scandinavia for not giving vitamin substitution was 2.8 (95% CI (1.9, 4.3)). This effect was statistically significant in Norway and Sweden, which use A and D vitamin supplementation, but not in Denmark, where only vitamin D supplementation is given. The odds ratios remained significant in Sweden when an adjustment was made for confounding factors (OR 28.4, 95% CI (4.7, 171.3)). CONCLUSION: We found an association between increased risk of sudden infant death syndrome and infants not being given vitamin supplementation during their first year of life. This was highly significant in Sweden, and the effect is possibly connected with vitamin A deficiency. This effect persisted when an adjustment was made for potential confounders, includingsocioeconomic factors.

No indications of increased quiet sleep in infants receiving care based on the newborn individualized developmental care and assessment program (NIDCAP).

UNLABELLED: It has been proposed that the developmentally supportive care of very-low-birthweight (VLBW) infants provided by the Newborn Individualized Developmental Care and Assessment Program (NIDCAP) can improve the infants' opportunities for rest and sleep. The aim of the present study was to determine whether quiet sleep (QS) in VLBW infants is affected by NIDCAP care. Twenty-two infants with a gestational age of <32 wk at birth randomly received either NIDCAP (n = 11) or conventional care (n = 11). These two groups were comparable (mean (SD)) with respect to birthweight (1021 (240) vs 913 (362)g, respectively) and gestational age (27.1 (1.7) vs 26.4 (1.8) wk). The infants in the NIDCAP group were cared for in a separate room by a group of specially trained nurses and subjected to weekly NIDCAP observations until they reached a postconceptional age (PCA) of 36 wk. Quiet sleep (QS) was assessed from 24-h amplitude-integrated EEGs recorded at 32 and 36 wk of PCA. The percentage of time [mean (SD)] spent in QS at 32 wk of PCA was 33.5 (2.6) % for the NIDCAP group and 33.3 (6.9) % for the control infants (ns). At 36 wk, the corresponding values were 24.5 (3.2) % and 25.7 (4.7) %, respectively (ns). The number of QS periods/24 h decreased equally in both groups in association with maturation: from 24.6 (3.3) to 16.8 (1.8) and from 25.0 (5.8) to 17.5 (3.3), at 32 wk, and 36 wk of PCA, respectively (NS). CONCLUSIONS: There were no indications of increased QS at 32 or 36 wk of postconceptional age among VLBW infants who received care based on NIDCAP.

Breast feeding and the sudden infant death syndrome in Scandinavia, 1992-95.

AIMS: To assess the effects of breast feeding habits on sudden infant death syndrome (SIDS). METHODS: The analyses are based on data from the Nordic Epidemiological SIDS Study, a case-control study in which parents of SIDS victims in the Scandinavian countries between 1 September 1992 and 31 August 1995 were invited to participate, each with parents of four matched controls. The odds ratios presented were computed by conditional logistic regression analysis. RESULTS: After adjustment for smoking during pregnancy, paternal employment, sleeping position, and age of the infant, the adjusted odds ratio (95% CI) was 5.1 (2.3 to 11.2) if the infant was exclusively breast fed for less than four weeks, 3.7 (1.6 to 8.4) for 4-7 weeks, 1.6 (0.7 to 3.6) for 8-11 weeks, and 2.8 (1.2 to 6.8) for 12-15 weeks, with exclusive breast feeding over 16 weeks as the reference. Mixed feeding in the first week post partum did not increase the risk. CONCLUSIONS: The study is supportive of a weak relation between breast feeding and SIDS reduction.

Biphasic effects of substance P on respiratory activity and respiration-related neurones in ventrolateral medulla in the neonatal rat brainstem in vitro.

The effects of substance P (SP) on respiratory activity in the brainstem-spinal cord preparation from neonatal rats (0-4 days old) were investigated. The respiratory activity was recorded from C4 ventral roots and intracellularly from three types of respiration-related neurones, i.e. pre-inspiratory (or biphasic E), three subtypes of inspiratory; expiratory and tonic neurones in the ventrolateral medulla (VLM). After the onset of SP bath application (10 nM-1 microM) a dose-dependent decline of burst rate (by 48%) occurred, followed by a weaker dose-dependent increase (by 17.5%) in burst rate. The biphasic effect of SP on inspiratory burst rate was associated with sustained membrane depolarization (in a range of 0.5-13 mV) of respiration-related and tonic neurones. There were no significant changes in membrane resistance in any type of neurones when SP was applied alone or when synaptic transmission was blocked with tetrodotoxin (TTX). The initial depolarization was associated with an increase in inspiratory drive potential (by 25%) as well as in bursting time (by 65%) and membrane excitability in inspiratory and pre-inspiratory neurones, which corresponded to the decrease in burst rate (C4 activity). The spiking frequency of expiratory and tonic neurones was also increased (by 36 and 48%). This activation was followed by restoration of the synaptic drive potential and bursting time in inspiratory and to a less extent in pre-inspiratory neurones, which corresponded to the increase in burst rate. The discharge frequency of expiratory and tonic neurones also decreased to control values. This phase followed the peak membrane depolarization. At the peak depolarization, SP reduced the amplitude of the action potential by 4-8% in all types of neurones. Our results suggest that SP exerts a general excitatory effect on respiration-related neurones and synaptic coupling within the respiratory network in the VLM. The transient changes in neuronal activity in the VLM may underlie the biphasic effect of SP in the brainstem respiration activity recorded in C4 roots. However, the biphasic effect of SP on inspiratory burst rate seems to be also defined by the balance in activity of other SP-sensitive systems and neurones in the respiratory network in the brainstem and spinal cord, which can modify the activity of medullary respiratory rhythm generator.

Cerebral hemodynamic response to unpleasant odors in the preterm newborn measured by near-infrared spectroscopy.

Newborn infants in intensive care units are exposed to several unfamiliar smells, mostly related to the nosocomial environment. How the preterm baby perceives these olfactory stimulations remains unclear. Near-infrared spectroscopy can be performed noninvasively above the olfactory cortex to monitor changes of cerebral blood flow as an indicator of cortical activation. The aim of this study was to explore by near-infrared spectroscopy how odorous substances routinely used in the neonatal intensive care unit influence bilateral cortical hemodynamics in the olfactory region of the brains of preterm infants. Specifically, a detergent (Neomidil) and an adhesive remover (Remove) have been tested. Twenty preterm neonates of gestational age 30-37 wk (mean 33.7 +/- 2.3 SD) and postconceptional age 32-37.3 wk (mean 35.5 +/- 2.75 SD) were monitored by near-infrared spectroscopy. Two optode pairs were placed above the anterior orbitofrontal gyri, which is involved in olfactory processing, on each side of the skull. Fifteen babies were exposed to the smell of a disinfectant and five babies to that of a detergent, both applied to small cotton pads. Changes of oxygenated Hb and deoxygenated Hb were recorded before, during, and after a 10-s stimulus. In 17 out of 20 babies, there was a decrease in oxygenated Hb and total Hb after the exposure to the substances. The decrease was significantly greater in the right side than in the left side. This change was different from that observed in our previous study after exposure to colostrum and the pleasant smell of vanilla, which elicited an increase in blood oxygenation in the same region. The biologic significance of this finding is unknown. We conclude that cortical hemodynamic modifications occur in the preterm newborn after exposure to preparations commonly used in the neonatal intensive care unit. A lateralization seems to occur in processing unpleasant olfactory cues.

Neurotransmitters and neuromodulators during early human development.

BACKGROUND: Neurotransmitters such as monoamines appear in the embryo before the neurones are differentiated. They may have other functions than neurotransmission during embryogenesis such as differentiation and neuronal growth. For example, serotonin may act as a morphogen. A number of neuropeptides are expressed during ontogenesis, but their function has been difficult to establish. Maybe some of them remain as evolutionary residues. Fast-switching neurotransmitters like the excitatory amino acids and the more ionotropic receptors dominate in the human brain, but appear probably later during evolution as well as during ontogeny. METHODS: The distribution of catecholamines during development has been analysed with a fluorescence method, while most of the other neurotransmitters have been mapped with immunohistochemical methods. The classical method to determine the physiological role of a neurotransmitter or modulator is to study the physiological effect of its antagonist, blocking the endogenous activity. By transgenic technique, the genes encoding for enzymes involved in the synthesis of neurotransmitters can be knocked-out. MAJOR FINDINGS: Pharmacological blocking of endogenous activity has, for example, demonstrated that adenosine suppresses fetal respiration. Knocking out the dopamine beta-hydroxylase gene results in fetal death, suggesting that noradrenaline is essential for survival. Some neurotransmitters change their effect during embryogenesis, e.g. GABA which is excitatory in the embryo, but inhibitory after birth due to a switch from a high to low chloride content in the nerve cells. It is possible that this is of importance for the wiring of neuronal network in early life. NMDA receptors dominate in the foetus, while kainate and AMPA receptors appear later. At birth, there is a surge of neurotransmitters such as catecholamines, which may be of importance for the neonatal adaptation. CONCLUSIONS: Neurotransmitters and modulators are not only important for the neural trafficking in the embryo, but also for the development of the neuronal circuits. Prenatal or neonatal stress (hypoxia), as well as various drugs, may disturb the wiring and cause long-term behavioural effects (fetal and neonatal programming).

Inhibition of macrophage proinflammatory cytokine expression by steroids and recombinant IL-10.

Chronic lung disease (CLD) of prematurity is a prolonged respiratory failure in very-low-birth-weight neonates. Proinflammatory cytokines have been implicated in the development of CLD. Steroids have been shown to produce some improvement in neonates with this disease. The purpose of this study was to evaluate the downregulation of these proinflammatory cytokines by dexamethasone, budesonide and recombinant IL-10 (rIL-10) in order to elucidate the mechanism of the clinical benefit of steroids in babies. Our results showed that dexamethasone, budesonide and rIL-10 significantly inhibited both IL-6 and TNF-alpha production in the THP-1 cell line stimulated by lipopolysaccharide and Ureaplasma urealyticum antigen. Similar effects were found in macrophages from tracheobronchial aspirate fluid from newborn infants. In the rat alveolar macrophage cell line, steroids inhibited IL-6 and TNF-alpha production, while rat rIL-10 did not significantly decrease production. In conclusion, steroids and human rIL-10 were able to downregulate proinflammatory cytokine production, which may explain the beneficial effect of steroids and suggests that rIL-10 could be tried as an anti-inflammatory agent in neonates with a high risk of CLD.

Organization of the neuronal circuits in the central nervous system during development.

UNLABELLED: The human brain is a product of genetic instructions, cellular interactions and influences of innate activity and external stimulation. The formation of the neural tube and the patterning of the brain are determined by homeotic genes. After a prosencephalic phase with the formation of the hemispheres, the neurons prolipherate to number about 100 billion halfway through gestation. They also migrate to their final positions in an inside-outside fashion with the newly formed neurons at the outer layer of the cortex, followed by synaptogenesis, programmed cell death and organization of the neuronal circuits. This phase is probably determined not only by genes but also by innate activity, which for example has been detected in the foetal retina: "Cells that fire together wire together while those which don't won't". CONCLUSION: Development of the neuronal circuits in the CNS can be viewed as epigenetic. i.e. many different components must come together at the right time and place.