Critical Period Of Brain Development Research Articles

Neuropsychological performance in young adults with cannabis use disorder.

Background and Aims:Cannabis is a commonly used recreational drug in young adults. The worldwide prevalence in 18- to 25-year-olds is approximately 35%. Significant differences in cognitive performance have been reported previously for groups of cannabis users. However, the groups are often heterogeneous in terms of cannabis use. Here, we study daily cannabis users with a confirmed diagnosis of cannabis use disorder (CUD) to examine cognitive performance on measures of memory, executive function and risky decision-making.Methods:Forty young adult daily cannabis users with diagnosed CUD and 20 healthy controls matched for sex and premorbid intelligence quotient (IQ) were included. The neuropsychological battery implemented was designed to measure multiple modes of memory (visual, episodic and working memory), risky decision-making and other domains of executive function using subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB).Results:Our results showed that young adult daily cannabis users with CUD perform significantly poorer on tasks of visual and episodic memory compared with healthy controls. In addition, executive functioning was associated with the age of onset.Conclusions:Further research is required to determine whether worse performance in cognition results in cannabis use or is a consequence of cannabis use. Chronic heavy cannabis use during a critical period of brain development may have a particularly negative impact on cognition. Research into the persistence of cognitive differences and how they relate to functional outcomes such as academic/career performance is required.

Iron and Neurodevelopment in Preterm Infants: A Narrative Review.

Iron is critical for brain development, playing key roles in synaptogenesis, myelination, energy metabolism and neurotransmitter production. NICU infants are at particular risk for iron deficiency due to high iron needs, preterm birth, disruptions in maternal or placental health and phlebotomy. If deficiency occurs during critical periods of brain development, this may lead to permanent alterations in brain structure and function which is not reversible despite later supplementation. Children with perinatal iron deficiency have been shown to have delayed nerve conduction speeds, disrupted sleep patterns, impaired recognition memory, motor deficits and lower global developmental scores which may be present as early as in the neonatal period and persist into adulthood. Based on this, ensuring brain iron sufficiency during the neonatal period is critical to optimizing neurodevelopmental outcomes and iron supplementation should be targeted to iron measures that correlate with improved outcomes.

From Neurodevelopmental to Neurodegenerative Disorders: The Vascular Continuum.

Structural and functional integrity of the cerebral vasculature ensures proper brain development and function, as well as healthy aging. The inability of the brain to store energy makes it exceptionally dependent on an adequate supply of oxygen and nutrients from the blood stream for matching colossal demands of neural and glial cells. Key vascular features including a dense vasculature, a tightly controlled environment, and the regulation of cerebral blood flow (CBF) all take part in brain health throughout life. As such, healthy brain development and aging are both ensured by the anatomical and functional interaction between the vascular and nervous systems that are established during brain development and maintained throughout the lifespan. During critical periods of brain development, vascular networks remodel until they can actively respond to increases in neural activity through neurovascular coupling, which makes the brain particularly vulnerable to neurovascular alterations. The brain vasculature has been strongly associated with the onset and/or progression of conditions associated with aging, and more recently with neurodevelopmental disorders. Our understanding of cerebrovascular contributions to neurological disorders is rapidly evolving, and increasing evidence shows that deficits in angiogenesis, CBF and the blood-brain barrier (BBB) are causally linked to cognitive impairment. Moreover, it is of utmost curiosity that although neurodevelopmental and neurodegenerative disorders express different clinical features at different stages of life, they share similar vascular abnormalities. In this review, we present an overview of vascular dysfunctions associated with neurodevelopmental (autism spectrum disorders, schizophrenia, Down Syndrome) and neurodegenerative (multiple sclerosis, Huntington’s, Parkinson’s, and Alzheimer’s diseases) disorders, with a focus on impairments in angiogenesis, CBF and the BBB. Finally, we discuss the impact of early vascular impairments on the expression of neurodegenerative diseases.

Cognitive and Affective Empathy as Indirect Paths Between Heterogeneous Depression Symptoms on Default Mode and Salience Network Connectivity in Adolescents.

Depression amongst adolescents is a prevalent disorder consisting of heterogeneous emotional and functional symptoms-often involving impairments in social domains such as empathy. Cognitive and affective components of empathy as well as their associated neural networks (default mode network for cognitive empathy and salience network for affective empathy) are affected by depression. Depression commonly onsets during adolescence, a critical period for brain development underlying empathy. However, the available research in this area conceptualizes depression as a homogenous construct, and thereby miss to represent the full spectrum of symptoms. The present study aims to extend previous literature by testing whether cognitive and affective empathy indirectly account for associations between brain network connectivity and heterogeneous depression symptoms in adolescents. Heterogeneous functional and emotional symptoms of depression were measured using the child depression inventory. Our results indicate that cognitive empathy mediates the association between default mode network functional connectivity and emotional symptoms of depression. More specifically, that adolescents with a stronger positive association between the default mode network and cognitive empathy show lower emotional depression symptoms. This finding highlights the importance of cognitive empathy in the relationship between brain function and depression symptoms, which may be an important consideration for existing models of depression in adolescents.

Adolescent Substance Abuse, Transgenerational Consequences and Epigenetics.

Adolescence is the transitional period between childhood and adulthood and a critical period in brain development. Adolescence in humans is also associated with increased expression of risk-taking behaviors. Epidemiological and clinical studies, for example, show a surge of drug abuse and raise the hypothesis that the adolescent brain undergoes critical changes resulting in diminished control. Determining how substance abuse during this critical period might cause long-term neurobiological changes in cognition and behavior is therefore critically important. The present work aims to provide an evaluation of the transgenerational and multi-generational phenotypes derived from parent animals exposed to drugs of abuse only during their adolescence. Specifically, we will consider changes found following the administration of cannabinoids, nicotine, alcohol and opiates. In addition, epigenetic modifications of the genome following drug exposure will be discussed as emerging evidence of the underlying adverse transgenerational effects. Notwithstanding, much of the new data discussed here is from animal models, indicating that future clinical studies are much needed to better understand the neurobiological consequences and mechanisms of drug actions on the human brains’ development and maturation.

Effects of early-life stress and sex on blood-brain barrier permeability and integrity in juvenile and adult rats.

Early-life stress (ELS) is considered a relevant etiological factor for neurodegenerative and mental disorders. In the present study, we hypothesized that ELS may persistently and sex dependently influence blood-brain barrier (BBB) integrity and function during critical periods of brain development and consequently determine susceptibility to and sex-related prevalence of chronic diseases in adult life. We used the maternal separation (MS) procedure in rats to model ELS and evaluated BBB permeability and gene expression of selected tight junction (TJ) proteins, glucose transporter type 1 (Slc2a1) and aquaporin 4 (Aqp4) in the medial prefrontal cortex (mPFC), dorsal striatum (dSTR) and hippocampus of juvenile and adult rats. Serum concentrations of a peripheral marker of BBB function (S100β) and proinflammatory cytokines were also assessed. We observed developmental sealing of the BBB and sex differences in the permeability of the BBB and the mRNA expression of TJ proteins and Slc2a1. Adult females showed lower BBB permeability and higher levels of Cldn3, Cldn5, Ocln, and Slc2a1 in the mPFC and dSTR than males. MS temporarily increased BBB permeability in the dSTR of juvenile males and affected mRNA expression of the majority of studied proteins related to BBB function in age-, region- and sex-dependent manners. Additionally, MS sex dependently decreased serum S100β levels and did not affect proinflammatory cytokine concentrations. In general, our study did not reveal a clear or strong negative effect of MS on BBB integrity. However, the results suggest that ELS may induce adaptive/maladaptive changes or compensatory mechanisms within the BBB of unknown yet consequences.

Prolonged morphine exposure during adolescence alters the responses of lateral paragigantocellularis neurons to naloxone in adult morphine\xa0dependent rats

IntroductionAdolescence is a critical period in brain development, and it is characterized by persistent maturational alterations in the function of central nervous system. In this respect, many studies show the non-medical use of opioid drugs by adolescents. Although this issue has rather widely been addressed during the last decade, cellular mechanisms through which adolescent opioid exposure may induce long-lasting effects are not duly understood. The present study examined the effect of adolescent morphine exposure on neuronal responses of lateral paragigantocellularis nucleus to naloxone in adult morphine-dependent rats.MethodsAdolescent male Wistar rats (31 days old) received increasing doses of morphine (from 2.5 to 25 mg/kg, twice daily, s.c.) for 10 days. Control subjects were injected saline with the same protocol. After a drug-free interval (20 days), animals were rendered dependent on morphine during 10 days (10 mg/kg, s.c., twice daily). Then, extracellular single-unit recording was performed to investigate neural response of LPGi to naloxone in adult morphine-dependent rats.ResultsResults indicated that adolescent morphine treatment increases the number of excitatory responses to naloxone, enhances the baseline activity and alters the pattern of firing in neurons with excitatory responses in adult morphine-dependent rats. Moreover, the intensity of excitatory responses is reduced following the early life drug intake.ConclusionIt seems that prolonged opioid exposure during adolescence induces long-lasting neurobiological changes in LPGi responsiveness to future opioid withdrawal challenges.

Age-related differences in resting state functional connectivity in pediatric migraine

BackgroundMigraine affects roughly 10% of youth aged 5–15 years, however the underlying mechanisms of migraine in youth are poorly understood. Multiple structural and functional alterations have been shown in the brains of adult migraine sufferers. This study aims to investigate the effects of migraine on resting-state functional connectivity during the period of transition from childhood to adolescence, a critical period of brain development and the time when rates of pediatric chronic pain spikes.MethodsUsing independent component analysis, we compared resting state network spatial maps and power spectra between youth with migraine aged 7–15 and age-matched controls. Statistical comparisons were conducted using a MANCOVA analysis.ResultsWe show (1) group by age interaction effects on connectivity in the visual and salience networks, group by sex interaction effects on connectivity in the default mode network and group by pubertal status interaction effects on connectivity in visual and frontal parietal networks, and (2) relationships between connectivity in the visual networks and the migraine cycle, and age by cycle interaction effects on connectivity in the visual, default mode and sensorimotor networks.ConclusionsWe demonstrate that brain alterations begin early in youth with migraine and are modulated by development. This highlights the need for further study into the neural mechanisms of migraine in youth specifically, to aid in the development of more effective treatments.

Chronic, Episodic Nicotine Alters Hypoglossal Motor Neuron Function at a Critical Developmental Time Point in Neonatal Rats.

Developmental nicotine exposure (DNE), alters brainstem neurons that control breathing, including hypoglossal motor neurons (XIIMNs), which innervate the tongue. Here, we tested the hypothesis that chronic, episodic DNE (eDNE), which mimics nicotine replacement therapies such as e-cigarettes or nicotine gum, alters the function of nicotinic acetylcholine receptors (nAChRs), XIIMN intrinsic properties, and tongue muscle function in vivo similar to what we have observed with a chronic, sustained exposure model. We delivered nicotine to pregnant Sprague Dawley rats through drinking water and studied pups of either sex in two age groups: postnatal day (P)1–P5 and P10–P12, which encompasses a critical period in brain development. At P1–P5, eDNE was associated with delayed recovery of nAChRs from desensitization; however, there were no changes in the magnitude of desensitization, XIIMN intrinsic properties, or tongue muscle function in vivo. By P10–P12, eDNE XIIMNs had lower peak firing frequencies in response to depolarizing current injection, larger delayed rectifier potassium currents, and continued to exhibit delayed nAChR recovery. Moreover, this age group exhibited a blunted and delayed tongue muscle response to nasal occlusion in vivo, indicating that changes to XIIMN intrinsic properties is an important mechanism behind this effect, as it is not produced by altered nAChR function alone. Together, these results show that eDNE alters XIIMNs and tongue muscle function during a critical period in brain development and that the specific effects of chronic nicotine exposure may be pattern dependent.

Comparing Evidence for Neurodevelopmental and Neurodegenerative Models of Schizophrenia: Do Effects of Schizophrenia Genetic Risk on Cortical Thickness and Cortical Surface Area Vary by Age?

Risk for schizophrenia peaks during late adolescence and early adulthood, a critical period for brain development (Häfner, 2003). Although several influential theoretical models have been proposed for the developmental relationship between brain pathology and clinical onset, to our knowledge, no study has directly evaluated the predictions of these models for schizophrenia developmental genetic effects on brain structure.

Longitudinal infant fNIRS channel-space analyses are robust to variability parameters at the group-level: An image reconstruction investigation

The first 1000 days from conception to two-years of age are a critical period in brain development, and there is an increasing drive for developing technologies to help advance our understanding of neurodevelopmental processes during this time. Functional near-infrared spectroscopy (fNIRS) has enabled longitudinal infant brain function to be studied in a multitude of settings. Conventional fNIRS analyses tend to occur in the channel-space, where data from equivalent channels across individuals are combined, which implicitly assumes that head size and source-detector positions (i.e. array position) on the scalp are constant across individuals. The validity of such assumptions in longitudinal infant fNIRS analyses, where head growth is most rapid, has not previously been investigated. We employed an image reconstruction approach to analyse fNIRS data collected from a longitudinal cohort of infants in The Gambia aged 5- to 12-months. This enabled us to investigate the effect of variability in both head size and array position on the anatomical and statistical inferences drawn from the data at both the group- and the individual-level. We also sought to investigate the impact of group size on inferences drawn from the data. We found that variability in array position was the driving factor between differing inferences drawn from the data at both the individual- and group-level, but its effect was weakened as group size increased towards the full cohort size (N = 53 at 5-months, N = 40 at 8-months and N = 45 at 12-months). We conclude that, at the group sizes in our dataset, group-level channel-space analysis of longitudinal infant fNIRS data is robust to assumptions about head size and array position given the variability in these parameters in our dataset. These findings support a more widespread use of image reconstruction techniques in longitudinal infant fNIRS studies.

Enriching activities during childhood are associated with variations in functional connectivity patterns later in life

Enriching early life experiences (e.g., sport, art, music, volunteering, language learning) during a critical period of brain development may promote structural and functional brain changes that are still present decades later (>60 years). We assessed whether a greater variety of enriching early life activities (EELA) before age 13 years were associated with individual differences in cortical and subcortical (hippocampus and amygdala) structure and function later in life (older adults aged 60–80 years). Results indicated no association between EELA and amygdala and hippocampus volumes, but higher functional connectivity between the amygdala and the insula was associated with more variety of EELA. EELA was not associated with cortical thickness controlling for sex, but sex-specific associations with the right pars opercularis were found. EELA was further associated with variations in functional connectivity patterns of the orbitofrontal cortex, driven by connecitivty to regions within the visual, somatosensory and limbic networks. Early life enriching activities appear to contribute to potential mechanisms of cognitive reserve (functional processes) more so than brain reserve (structure) later in life.

The downstream effects of forced exercise training and voluntary physical activity in an enriched environment on hippocampal plasticity in preadolescent rats

During critical periods of brain development, exercise-induced physical fitness may greatly impact the brain structure and function. Nevertheless, forced and intensive physical activities may display negative effects, particularly in the pre-pubertal period. Preadolescent rats were exposed to an enriched environment and combined exercise training for three consecutive weeks in the present study. There was a large cage with enriching stimuli and voluntary physical activity opportunities as an enriched environment (EE). The combined exercise training (CET) consisted of aerobic and resistance training programs. The protein levels of corticosterone (CORT), glucocorticoid receptors (GRs), insulin-like growth factor-1 (IGF-1), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) were assessed using Enzyme-linked immunosorbent assay and western blotting. Cresyl violet staining was also used to evaluate the number of cells in the hippocampus. While GRs levels were significantly increased in both EE and CET groups (P < 0.001), decreased CORT levels were found in enriched rats (P < 0.05). Moreover, elevated BDNF levels were found in the EE (P < 0.01) and CET (P < 0.05) groups. Similarly, VEGF significantly increased in the EE (P < 0.01) and CET (P < 0.05) animals. However, IGF-1 levels were high only in trained rats (P < 0.05). The number of cells also significantly increased in the DG and CA1 region of the hippocampus after each intervention (P < 0.001). These findings clarified that combined exercise training and voluntary physical activity in an enriched environment during the preadolescent period might promote the downstream plasticity effects on the hippocampus.

Audiovisual overstimulation in childhood and adolescence promotes hyperactive behaviour in adult mice

There is a discussion about the impact of technological development on behavioural aspects, a nuance that the present study aimed to assess. p21, p26 and p36 mice were subjected to audio (70 db) and visual stimulation (flashing lights) for 2 or 6 h per day until p64. Naive animals were included. From p74 onwards, the animals were subjected to tests to assess their locomotion, depression, anxiety, aggressiveness, and nociception behaviours. Weight assessment was also performed. The animals that received stimulation for 2 h a day since p21 showed a decrease in rearing and grooming behaviour in the open field test, as well as in the mechanical orofacial sensitivity. Animals that received stimulation for 6 h daily since p21 showed increased locomotor activity in the open field test. Animals that received stimulation for 2 h a day since p26 showed an increase in locomotor activity and a decrease in grooming behaviour in the open field test, in addition to a reduction in the number of entries in the closed arm of the elevated plus maze. Animals stimulated from p26 for 6 h daily increased the reaction time to the thermal stimulus. Animals that received stimulation for 2 h daily since p36 showed an increase in locomotor activity and a decrease in grooming behaviour in the open field test. Taken together, these findings suggest that audiovisual overstimulation during critical periods of brain development may have adverse effects compatible with hyperactivity in adulthood.

Down syndrome is an oxidative phosphorylation disorder

Down syndrome is the most common genomic disorder of intellectual disability and is caused by trisomy of chromosome 21. Several genes in this chromosome repress mitochondrial biogenesis. The goal of this study was to evaluate whether early overexpression of these genes may cause a prenatal impairment of oxidative phosphorylation negatively affecting neurogenesis. Reduction in the mitochondrial energy production and a lower mitochondrial function have been reported in diverse tissues or cell types, and also at any age, including early fetuses, suggesting that a defect in oxidative phosphorylation is an early and general event in Down syndrome individuals. Moreover, many of the medical conditions associated with Down syndrome are also frequently found in patients with oxidative phosphorylation disease. Several drugs that enhance mitochondrial biogenesis are nowadays available and some of them have been already tested in mouse models of Down syndrome restoring neurogenesis and cognitive defects. Because neurogenesis relies on a correct mitochondrial function and critical periods of brain development occur mainly in the prenatal and early neonatal stages, therapeutic approaches intended to improve oxidative phosphorylation should be provided in these periods.

Adolescent opioid abuse: Role of glial and neuroimmune mechanisms.

Opioids are widely prescribed for pain management, and prescription opioid misuse in adolescents has become a major epidemic in the United States and worldwide. Emerging data indicate that adolescence represents a critical period of brain development, and exposure to opioids during adolescence may increase the risk of addiction in adulthood. There is growing evidence that disruptions in brain glial function may be implicated in numerous chronic neuropathologies. Evidence suggests that glial mechanisms have an important role in the development and maintenance of opioid abuse and the risk for addiction. This review will describe glial and neuroimmune mechanisms involved in opioid use disorders during adolescence, which may increase substance use disorder liability later in life. Moreover, this review will identify some important neuro-glial targets, involved in opioid abuse and addiction, to develop future preventions and treatment strategies.

Regulation of glutamate signaling in the extended amygdala by adolescent alcohol exposure.

Adolescence is a critical period for brain development and behavioral maturation, marked by increased risk-taking behavior and the initiation of drug use. There are significant changes in gray matter volume and pruning of synapses along with a shift in excitatory to inhibitory balance which marks the maturation of cognition and decision-making. Because of ongoing brain development, adolescents are particularly sensitive to the detrimental effects of drugs, including alcohol, which can cause long-lasting consequences into adulthood. The extended amygdala is a region critically implicated in withdrawal and negative affect such as anxiety and depression. As negative affective disorders develop during adolescence, the effects of adolescent alcohol exposure on extended amygdala circuitry needs further inquiry. Here we aim to provide a framework to discuss the existing literature on the extended amygdala, the neuroadaptations which result from alcohol use, and the intersection of factors which contribute to the long-lasting effects of this exposure.

An examination of roles and responsibilities of paraprofessionals in the education and care of infants and toddlers: A contribution to their initial training.

Significant advances in psychology and neuroscience research has contributed to a deepened understanding that the first two years of life are a critical period for brain development. The lack of stimulating experiences produces deficits in physical, cognitive and especially emotional health of babies. For this reason, it is essential to provide intentional pedagogical experiences to children from birth to two years old, through quality early childhood education. This, however, requires competent and well-trained professionals and paraprofessionals, whose preparation and learning opportunities are aligned with the roles and responsibilities they must fulfill in their professional lives. The objective of this study was to explore, through interviews with paraprofessionals and literature reviews, the roles and responsibilities of Chilean practitioners who work with infants and toddlers, and compare these results with the initial training curriculum. Both convergences and discrepancies were found, which enabled the elaboration of recommendations for initial training and public policies in early childhood education.

Impact of Prenatal Hypoxia on the Development and Behavior of the Rat Offspring

The healthy development of the fetus depends on the exact course of pregnancy and delivery. Therefore, prenatal hypoxia remains between the greatest threats to the developing fetus. Our study aimed to assess the impact of prenatal hypoxia on postnatal development and behavior of the rats, whose mothers were exposed to hypoxia (10.5 % O2) during a critical period of brain development on GD20 for 12 h. This prenatal insult resulted in a delay of sensorimotor development of hypoxic pups compared to the control group. Hypoxic pups also had lowered postnatal weight which in males persisted up to adulthood. In adulthood, hypoxic males showed anxiety-like behavior in the OF, higher sucrose preference, and lower levels of grimace scale (reflecting the degree of negative emotions) in the immobilization chamber compared to the control group. Moreover, hypoxic animals showed hyperactivity in EPM and LD tests, and hypoxic females had reduced sociability compared to the control group. In conclusion, our results indicate a possible relationship between prenatal hypoxia and changes in sociability, activity, and impaired emotion regulation in ADHD, ASD, or anxiety disorders. The fact that changes in observed parameters are manifested mostly in males confirms that male sex is more sensitive to prenatal insults.

Voluntary exercise ameliorates synaptic pruning deficits in sleep-deprived adolescent mice

Adolescence is a critical period for brain development and adequate sleep during this period is essential for physical function and mental health. Emerging evidence has detailed the neurological impacts of sleep insufficiency on adolescents, as was unveiled by our previous study, microglia, one of the crucial contributors to synaptic pruning, is functionally disrupted by lack of sleep. Here, we provided evidence featuring the protective effect and the underlying mechanisms of voluntary exercise (VE) on microglial functions in an adolescent 72 h sleep deprivation (SD) model. We identified that the aberrant hippocampal neuronal activity and impaired short-term memory performance in sleep-deprived mice were prevented by 11 days of VE. VE significantly normalized the SD-induced dendritic spine increment and maintained the microglial phagocytic ability in sleep-deprived mice. Moreover, we found that the amendment of the noradrenergic signal in the central nervous system may explain the preventative effects of VE on the abnormalities of microglial and neuronal functions caused by SD. These data suggested that VE may confer protection to the microglia-mediated synaptic pruning in the sleep-deprived adolescent brains. Therefore, physical exercise could be a beneficial health practice for the adolescents that copes the adverse influence of inevitable sleep insufficiency.