Period Of Early Brain Development Research Articles

Role of oxidative stress in the pathogenesis of autism spectrum disorders

The literature review reflects the contemporary information on the role of oxidative stress in the pathogenesis of autism spectrum disorders. We present data on the importance of genetic predisposition, environmental factors, and epigenetic influences on the development of oxidative stress, which, during critical periods of early brain development, may influence the induction and progression of the disease. The role of mitochondrial dysfunction, immunological disorders, increased permeability of the blood-brain barrier, hypoperfusion of the brain causing or aggravating the redox imbalance in patients with autism spectrum disorders is shown. Analysis of the literature data indicates that the increased content of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione, ceruloplasmin and transferrin in the blood and brain of patients with autism spectrum disorders reflects the activation of compensatory mechanisms. Increased levels of malondialdehyde, xanthine oxidase, nitric oxide in various biological media indicate insufficiency of antioxidant protection system. Taking into account the role of oxidative stress in the pathogenesis of autism spectrum disorders, therapy including antioxidant drugs is indicated for correction of metabolic disorders.

Impact of Key Nutrients on Brain and Executive Function Development in Infants and Toddlers: A Narrative Review

Executive function skills are an essential aspect of cognition and are influenced in early life by multiple factors. One of the significant factors that influence brain development is nutrition, which plays a specific role in the brain’s developmental processes and functioning from fetal to adult age. Infants in their early life rely on breastmilk for nutrition. Knowledge of the composition of breast milk and the biochemical composition of the brain has led to the identification of critical nutrients needed for the brain’s growth, development, and functioning. Key nutrients for brain development are those that, when deficient during the precise, sensitive periods of early brain development, could have long-term adverse effects on brain functioning. This narrative review highlights the importance of some key nutrients in early brain development and executive functions, including cognitive performances in infants and toddlers. Lipids are crucial for brain development. Long-chain polyunsaturated fatty acids (LC-PUFA) and sphingomyelin are the key ingredients to influence cognitive performance potentially. Early development of executive function precursors in infants and toddlers is an essential foundation for executive functions outcomes in early childhood or adulthood. Evidence suggests that specific nutrients such as phospholipids, including sphingomyelin and LC-PUFAs (docosahexaenoic acid), are essential for developing higher-level cognitive functions.

Iron supplementation given to nonanemic infants: neurocognitive functioning at 16 years

ABSTRACT Objective There is concern that high iron uptake during the critical period of early brain development carries potential risks, especially for nonanemic infants. This study examined the neurocognitive functioning of 16-year-olds who were nonanemic as infants and received iron supplementation. Methods We studied 562 Chilean adolescents (M 16.2 years; 52.7% female) who participated in a randomized controlled iron supplementation trial in infancy. Between 6 and 12 months, 346 consumed an iron-fortified formula (12.7 Fe mg/L) or, if primarily breastfed, liquid vitamins with 15 mg elemental iron as ferrous sulfate, and 216 consumed unmodified cow milk without iron or liquid vitamins without iron if primarily breastfed. Results Compared to adolescents in the no-added iron condition in infancy, those in the iron-supplemented condition had poorer visual-motor integration, quantitative reasoning skills, and incurred more errors on neurocognitive tasks. Consuming larger amounts of iron-fortified formula in infancy was associated with lower arithmetic achievement. Of adolescents who had high hemoglobin at 6 months (Hb ≥ 125 g/L), those in the iron supplemented condition had poorer performance on arithmetic, quantitative reasoning, and response inhibition tests than those in the no-added iron condition. Of adolescents who had marginally low 6-month hemoglobin (Hb > 100 and < 110 g/L), those who received no-added iron incurred more errors on a visual searching task than those in the iron-supplemented condition. Conclusion The physiologic need for iron during the period of rapid and critical brain development in young infants should be considered vis-à-vis the risks associated with supplementing nonanemic infants with high levels of iron. Clinical Trials number: NCT01166451

L-type calcium channel contributions to intrinsic excitability and synaptic activity during basolateral amygdala postnatal development.

The amygdala contributes toward emotional processes such as fear, anxiety, and social cognition. Furthermore, evidence suggests that increased excitability of basolateral amygdala (BLA) principal neurons underlie certain neuropsychiatric disorders. Gain-of-function mutations in neuronal L-type calcium channels (LTCCs) are linked to neurodevelopmental diseases, including autism spectrum disorders (ASDs). While LTCCs are expressed throughout the BLA, direct evidence for increased LTCC activity affecting BLA excitability and potentially contributing to disease pathophysiology is lacking. In this study, we utilized a pharmacological approach to examine the contributions of LTCCs to BLA principal cell excitability and synaptic activity at immature (postnatal day 7, P7) and juvenile (P21) developmental stages. Acute upregulation of LTCC activity in brain slices by application of the agonist (S)-Bay K 8644 resulted in increased intrinsic excitability properties including firing frequency response, plateau potential, and spike-frequency adaptation selectively in P7 neurons. Contrastingly, for P21 neurons, the main effect of (S)-Bay K 8644 was to enhance burst firing. (S)-Bay K 8644 increased spontaneous inhibitory synaptic currents at both P7 and P21 but did not affect evoked synaptic currents at either stage. (S)-Bay K 8644 did not alter P7 spontaneous excitatory synaptic currents, although it increased current amplitude in P21 neurons. Overall, the results provide support for the notion that alteration of LTCC activity at specific periods of early brain development may lead to functional alterations to neuronal network activity and subsequently contribute to underlying mechanisms of amygdala-related neurological disorders.NEW & NOTEWORTHY The role of L-type calcium channels (LTCCs) in regulating neuronal electrophysiological properties during development remains unclear. We show that in basolateral amygdala principal neurons, an increase of LTCC activity alters both neuronal excitability and synaptic activity. The results also provide evidence for the distinct contributions of LTCCs at different stages of neurodevelopment and shed insight into our understanding of LTCC dysfunction in amygdala-related neurological disorders.

Structural network topology correlates of microstructural brain dysmaturation in term infants with congenital heart disease.

Neonates with complex congenital heart disease (CHD) demonstrate microstructural brain dysmaturation, but the relationship with structural network topology is unknown. We performed diffusion tensor imaging (DTI) in term neonates with CHD preoperatively (N = 61) and postoperatively (N = 50) compared with healthy term controls (N = 91). We used network topology (graph) analyses incorporating different weighted and unweighted approaches and subject-specific white matter segmentation to investigate structural topology differences, as well as a voxel-based analysis (VBA) to confirm the presence of microstructural dysmaturation. We demonstrate cost-dependent network inefficiencies in neonatal CHD in the pre- and postoperative period compared with controls, related to microstructural differences. Controlling for cost, we show the presence of increased small-worldness (hierarchical fiber organization) in CHD infants preoperatively, that persists in the postoperative period compared with controls, suggesting the early presence of brain reorganization. Taken together, topological microstructural dysmaturation in CHD infants is accompanied by hierarchical fiber organization during a protracted critical period of early brain development. Our methodology also provides a pipeline for quantitation of network topology changes in neonates and infants with microstructural brain dysmaturation at risk for perinatal brain injury.

Design and rationale of the “Sedation strategy and cognitive outcome after critical illness in early childhood” study

There is increasing concern that sedatives commonly used during critical illness may be neurotoxic during the period of early brain development. The Sedation strategy and cognitive outcome after critical illness in early childhood (RESTORE-cognition) study is a prospective cohort study designed to examine the relationships between sedative exposure during pediatric critical illness and long-term neurocognitive outcomes. We assess multiple domains of neurocognitive function 2.5–5 years post-hospital discharge, at a single time point and depending on participant and clinician availability, in up to 500 subjects who had normal baseline cognitive function, were aged 2 weeks to 8 years at pediatric intensive care unit admission, and were enrolled in a cluster randomized controlled trial of a sedation protocol (the RESTORE trial; U01 HL086622 and HL086649). In addition, to provide comparable data on an unexposed group with similar baseline biological characteristics and environment, we are studying matched, healthy siblings of RESTORE patients. Our goal is to increase understanding of the relationships between sedative exposure, critical illness, and long-term neurocognitive outcomes in infants and young children by studying these subjects 2.5 to 5 years after their index hospitalization. This paper highlights the design challenges in conducting comprehensive neurocognitive assessment procedures across a broad age span at multiple testing centers across the United States. Our approach, which includes building interprofessional teams and novel cohort retention strategies, may be of help in future longitudinal trials.

Sex-specific epigenetic programming by gestational stress

Stress during specific developmental stages can alter the trajectory of normal neurodevelopmental processes, often leading to dysfunctional stress responsiveness, cognitive and metabolic disruptions later in life. Here we summarize our current knowledge of the effects of stress exposure during key periods of early brain development and the potential mechanisms by which stress imparts long-term changes in the developing brain. We describe the potential for lifetime stress exposures to alter the parental germ line and ultimately alter offspring brain programming. We discuss the mechanisms by which prenatal and early postnatal stress program the brain, highlighting the importance of the placenta in transmitting maternal stress signals to the developing fetus. Finally, we highlight the emerging role of the stress-sensitive gut microbiome in programming the gut-brain axis to ultimately influence brain function and behavior.

Comparison of the developmental milestones and preweaning neurobehavioral parameters in rat pups exposed to lead (Pb) during gestation, lactation and pregestation period

Studies in urban children exposed to low lead (Pb) have shown neurobehavioral deficits in the domains of intelligence, reaction time and attention. The structures – hippocampus (vital for learning and memory) and cerebellum (play a role in motor behavior and cognition) – which develop postnatally, are affected by developmental Pb exposure. The effect of low level of Pb exposure during specific periods of early brain development on early neurobehavioral outcomes in rat pups has not been studied. So in this study, pregnant albino Wistar strain rats were exposed to low levels of Pb in drinking water during gestation period (G group), lactation period (L group), both gestation and lactation period (GL group) and prior to pregnancy (a period of 1 month) (PG group). The rat pups born in each of these groups were assessed in preweaning neurobehavioral parameters including surface righting reflex, swimming development, negative geotaxis and ascending wire mesh test. The swimming development scores were low in the GL group of rats. The negative geotaxis score in GL and G groups were altered. The day of achievement of ascending wire mesh test was significantly delayed in GL, G and L groups of rats. To conclude, results show that (a) low level of Pb exposure during gestation and lactation period of brain development causes significant alterations in the early neurobehavioral and sensorimotor reflex development in the absence of concomitant weight loss and (b) gestation period only and lactation period only, Pb exposure causes alteration in some of the neurobehavioral outcomes.

Gestational marginal zinc deficiency impaired fetal neural progenitor cell proliferation by disrupting the ERK1/2 signaling pathway

This study investigated if a marginal zinc deficiency during gestation in rats could affect fetal neural progenitor cell (NPC) proliferation through a down-regulation of the extracellular signal-regulated kinase (ERK1/2) signaling pathway. Rats were fed a marginally zinc-deficient or adequate diet from the beginning of gestation until embryonic day (E)19. The proportion of proliferating cells in the E19 fetal ventricular zone was decreased by marginal zinc deficiency. Immunostaining for phosphorylated ERK1/2 in the cerebral cortex was decreased in the marginal zinc fetuses, and this effect was strongest in the ventricular zone. Furthermore, phosphorylation of the upstream mitogen-activated ERK kinases (MEK1/2) was not affected, suggesting that marginal zinc deficiency could have increased ERK-directed phosphatase activity. Similar findings were observed in cultured rat embryonic cortical neurons and in IMR-32 neuroblastoma cells, in which zinc-deficiency decreased ERK1/2 phosphorylation without affecting MEK1/2 phosphorylation. Indeed, zinc deficiency increased the activity of the ERK-directed phosphatase protein phosphatase 2A (PP2A) in the fetal cortex and IMR-32 cells. Inhibition of PP2A with okadaic acid prevented the decrease in ERK phosphorylation and proliferation of zinc-deficient IMR-32 cells. Together these results demonstrated that decreased zinc availability reduces ERK1/2 signaling and decreased NPC proliferation as a consequence of PP2A activation. Disruption of fetal neurogenesis could underlie irreversible neurobehavioral impairments observed after even marginal zinc nutrition during a critical period of early brain development.

Evaluation of passive avoidance learning and spatial memory in rats exposed to low levels of lead during specific periods of early brain development.

Widespread use of heavy metal lead (Pb) for various commercial purposes has resulted in the environmental contamination caused by this metal. The studies have shown a definite relationship between low level lead exposure during early brain development and deficit in children's cognitive functions. This study investigated the passive avoidance learning and spatial learning in male rat pups exposed to lead through their mothers during specific periods of early brain development. Experimental male rats were divided into 5 groups: i) the normal control group (NC) (N = 12) consisted of rat offspring born to mothers who were given normal drinking water throughout gestation and lactation, ii) the pre-gestation lead exposed group (PG) (N = 12) consisted of rat offspring, mothers of these rats had been exposed to 0.2% lead acetate in the drinking water for 1 month before conception, iii) the gestation lead exposed group (G) (N = 12) contained rat offspring born to mothers who had been exposed to 0.2% lead acetate in the drinking water throughout gestation, iv) the lactation lead exposed group (L) (N = 12) had rat offspring, mothers of these rats exposed to 0.2% lead acetate in the drinking water throughout lactation and v) the gestation and lactation lead exposed group (GL) (N = 12) contained rat offspring, mothers of these rats were exposed to 0.2% lead acetate throughout gestation and lactation. The study found deficit in passive avoidance learning in the G, L and GL groups of rats. Impairment in spatial learning was found in the PG, G, L and GL groups of rats. Interestingly, the study found that gestation period only and lactation period only lead exposure was sufficient to cause deficit in learning and memory in rats. The extent of memory impairment in the L group of rats was comparable with the GL group of rats. So it can be said that postnatal period of brain development is more sensitive to neurotoxicity compared to prenatal exposure.

Assessment of oxidative stress in hippocampus, cerebellum and frontal cortex in rat pups exposed to lead (Pb) during specific periods of initial brain development.

Epidemiological studies in children have proved that lead (Pb) exposure causes deficits in neural and cognitive functions. The present study assessed the oxidative stress on postnatal day 30, in the hippocampus, cerebellum and frontal cortex of rat pups exposed to Pb during specific periods of early brain development. Five groups of rat pups were investigated, and 0.2% Pb acetate in drinking was the dosage used. (i) Gestation and lactation (GL) group (n = 9) of rat pups was exposed to Pb during gestation and lactation through their mother, (ii) gestation (G) group (n = 9) of rat pups was exposed to Pb during gestation only, (iii) lactation (L) group (n = 9) of rat pups was exposed to Pb during lactation only, (iv) pre-gestation (PG) group (n = 9) of rat pups was born to mothers who were exposed to Pb for 1 month before conception, and (v) normal control (NC) (n = 9) group of rats pups had no exposure to Pb during gestation and lactation period. From the present study, it is evident that Pb exposure during different periods of early brain development (GL, G, L and PG groups) causes oxidative stress and lactation period (postnatal period) of Pb exposure produces maximum oxidative stress.

Histological study on hippocampus, amygdala and cerebellum following low lead exposure during prenatal and postnatal brain development in rats.

Neuropsychological studies in children who are exposed to lead during their early brain development have shown to develop behavioural and cognitive deficit. The aim of the present study was to assess the cellular damage in hippocampus, amygdala and cerebellum of rat pups exposed to lead during different periods of early brain development. Five groups of rat pups were investigated. (a) Control group (n = 8) (mothers of these rats were given normal drinking water throughout gestation and lactation), (b) pregestation lead-exposed group (n = 8) (mothers of these rats were exposed to 0.2% lead acetate in the drinking water for one month before conception), (c) gestation lead-exposed group (n = 8) (exposed to 0.2% lead acetate in the drinking water through the mother throughout gestation [gestation day 01 to day 21]), (d) lactation lead-exposed group (n = 8) (exposed to 0.2% lead acetate in the drinking water through the mother throughout lactation [postnatal day 01 to day 21]) and (e) gestation and lactation lead-exposed group (n = 8) (exposed to 0.2% lead acetate throughout gestation and lactation). On postnatal day 30, rat pups of all the groups were killed. Numbers of surviving neurons in the hippocampus, amygdala and cerebellum regions were counted using cresyl violet staining technique. Histological data indicate that lead exposure caused significant damage to neurons of hippocampus, amygdala and cerebellum regions in all lead-exposed groups except lactation lead-exposed group. The extent of damage to neurons of hippocampus, amygdala and cerebellum regions in lactation lead-exposed group was comparable to gestation and lactation groups even though the duration of lead exposure was much less in lactation lead-exposed group. To conclude, the postnatal period of brain development seems to be more vulnerable to lead neurotoxicity compared to prenatal period of brain development.

Histological Study On Hippocampus Following Low Lead Exposure During Prenatal And Postnatal Brain Development In Rats.

Background: Neuropsychological studies in children who are exposed to lead have confirmed its detrimental effects on behavioral and cognitive development. However there is inconsistency in information on the crucial period of brain development as far as lead neurotoxicity is concerned. Aims: To assess the cellular damage in hippocampus of rat pups exposed to lead during different periods of early brain development. Methods: Four groups of rat pups were investigated. (a) control group (n=6) (mothers of these rats were given normal drinking water throughout gestation), (b) Gestation lead exposed group (n=6) (exposed to 0.2% lead acetate in the drinking water through the mother throughout gestation [gestation day 01 to day 21]), (c) Lactation lead exposed group (n=6) (exposed to 0.2% lead acetate in the drinking water through the mother throughout lactation [postnatal day 01 to day 29]), (d) Gestation and lactation lead exposed group (n=6) (exposed to 0.2% lead acetate throughout gestation and lactation). On postnatal day 30, rat pups of all the groups were sacrificed. Numbers of surviving neurons in the CA3 and dentate gyrusregions of hippocampus were counted following cresyl violet staining. The significance of differences among the groups were assessed using one way analysis of variance (ANOVA) test followed by Bonferroni multiple comparison test.P values &lt; 0.05 were considered as significant. Results: Hippocampal histological data indicate that lead exposure caused significant damage to neurons of CA3 and dentate gyrus in all lead exposed groups and the extent of damage to neurons of CA3 and dentate gyrus of Lactation group was comparable to Gestation and lactation group. Conclusion: Postnatal period of brain development seems to be more vulnerable to lead neurotoxicity as it had shown significant hippocampal damage even though period of exposure was less compared to Gestation and lactation group.

Motor and cognitive outcome at school age of children with surgically treated intestinal obstructions in the neonatal period

BackgroundThe motor and cognitive outcome at school age of newborn children with surgically treated intestinal obstructions is unknown. Physiological stress and anesthesia may potentially be harmful in the period of early brain development in newborn infants. ObjectiveTo determine motor and cognitive outcome at school age in children with surgically treated intestinal obstructions as newborns, and to identify clinical risk factors for adverse outcome. Study designCohort study of infants born between 1995 and 2002 with atresia, stenosis, or intestinal malrotation. At 6 to 13years we assessed their motor functions, intelligence, attention, visual perception, visuomotor integration, and verbal memory. ResultsOf 44 children three (7%) died. Twenty-seven survivors (66%) were included for follow-up (median gestational age 36.7weeks, birth weight 3000g). Motor outcome was abnormal (<5th percentile) in 22% of the children, which was significantly more than in the norm population (P<0.01). Scores on selective attention were abnormal in 15% of the children (P<0.01). Other cognitive functions were not affected. Lower birth weight and intestinal perforation were risk factors for poorer motor outcome (R2=53.0%), intrauterine growth restriction was a risk factor for poorer selective attention (R2=36.6%). ConclusionsChildren treated surgically for intestinal obstructions in the neonatal period had an increased risk for poor motor functioning and selective attention at school age. Low birth weight, intrauterine growth restriction and intestinal perforation were risk factors for adverse outcome. We recommend to closely follow the motor and attentional development of these children.

Evidence on the emergence of the brain's default network from 2-week-old to 2-year-old healthy pediatric subjects.

Several lines of evidence have implicated the existence of the brain's default network during passive or undirected mental states. Nevertheless, results on the emergence of the default network in very young pediatric subjects are lacking. Using resting functional magnetic resonance imaging in healthy pediatric subjects between 2 weeks and 2 years of age, we describe the temporal evolution of the default network in a critical, previously unstudied, period of early human brain development. Our results demonstrate that a primitive and incomplete default network is present in 2-week-olds, followed by a marked increase in the number of brain regions exhibiting connectivity, and the percent of connection at 1 year of age. By 2 years of age, the default network becomes similar to that observed in adults, including medial prefrontal cortex (MPFC), posterior cingulate cortex/retrosplenial (PCC/Rsp), inferior parietal lobule, lateral temporal cortex, and hippocampus regions. While the anatomical representations of the default network highly depend on age, the PCC/Rsp is consistently observed at in both age groups and is central to the most and strongest connections of the default network, suggesting that PCC/Rsp may serve as the main "hub" of the default network as this region does in adults. In addition, although not as remarkable as the PCC/Rsp, the MPFC also emerges as a potential secondary hub starting from 1 year of age. These findings reveal the temporal development of the default network in the critical period of early brain development and offer new insights into the emergence of brain default network.

Lifespan longitudinal multitasking by cortical neurons

The large number of neurons (1011) and synapses (1014) in the mammalian brain provides a rich anatomical substrate for information processing. Many neurons perform very specialized functions, such as detecting or processing sensory stimuli, relaying or amplifying attributes of an afferent input to another brain area or making decisions to convert inputs into action. Some cell types, including the early-generated subplate cells of the developing cerebral cortex, play a special role during a restricted period of early brain development, acting transiently as scaffolds for the formation of thalamocortical and corticothalamic connections. However, many of these neurons (10–20%) survive elimination and become functionally integrated into the mature cortical circuitry. Thus, a single neuron type can perform different functions in the brain at different periods of life, potentially increasing the combinatorial capacity of the functional cellular architecture of the brain over the lifespan.

ADVANCES OF NEUROIMAGING: STRUCTURE AND FUNCTION

Objectives: Cerebral palsy (CP) is one of the commonest forms of severe childhood disability. Recent evidence from neuroimaging suggests that CP, in the majority of cases, is due to brain lesions acquired during different periods of early brain development. CP – as a well defined form of early lesional encephalopathy – offers an ideal model to study brain plasticity, e.g. functional consequences of early brain lesions as well as compensatory mechanisms.

Note added to ‘Histamine metabolites in cerebrospinal fluid of patients with chronic schizophrenia: Their relationships to levels of other aminergic transmitters and ratings of symptoms’ Schizophrenia Research 14 (2) 1995 pp 93–104

The kynurenine pathway of tryptophan degradation generates several neuroactive compounds. Of those, kynurenic acid is an N-methyl-d-aspartate (NMDA) and alpha7 nicotinic receptor antagonist. The kynurenic acid hypothesis of schizophrenia is built upon the fact that kynurenic acid blocks glutamate receptors and is elevated in schizophrenia. Kynurenic acid tightly controls glutamatergic and dopaminergic neurotransmission and elevated brain levels appear related to psychotic symptoms and cognitive impairments. Contributing to enhanced production of kynurenic acid, the expression and enzyme activity of kynurenine 3-monooxygenase (KMO) are reduced in schizophrenia and in bipolar patients with a history of psychosis. The kynurenine pathway is also critically regulated by cytokines, and, indeed, the pro-inflammatory cytokines interleukin (IL)-1β and IL-6 are elevated in schizophrenia and bipolar disorder and stimulate the production of kynurenic acid. One physiological mechanism controlling the activity of the kynurenine pathway originates from the protein sorting nexin 7 (SNX7). This glial signaling pathway initiates a caspase-8-driven activation of IL-1β that induces tryptophan-2,3-dioxygenase 2 (TDO2), an enzyme in the kynurenine pathway. A recent study shows that a genetic variation resulting in decreased expression of SNX7 is linked to increased central levels of kynurenic acid and ultimately to psychosis and cognitive dysfunction in bipolar disorder. Experimental studies highlight the detrimental effects of increased synthesis of kynurenic acid during sensitive periods of early brain development. Furthermore, experimental studies strongly support inhibition of kynurenine aminotransferase (KAT) II as a novel target and a valuable pharmacological strategy in the treatment of psychosis and for improving cognitive performance relevant for schizophrenia.This article is part of the Special Issue entitled ‘The Kynurenine Pathway in Health and Disease’.