REVIEW | doi:10.20944/preprints202210.0189.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: acetaminophen; autism; paracetamol; neurodevelopment
Online: 13 October 2022 (08:00:33 CEST)
Evidence that early life exposure to acetaminophen causes neurodevelopmental injury in susceptible children has mounted for more than a decade. Evidence is diverse, including extensive work with laboratory animals, otherwise unexplained associations, factors associated with the metabolism of acetaminophen, and some limited studies in humans. Although evidence has reached an overwhelming level and has been reviewed in detail recently, some controversy remains. In this narrative review, some of those controversies are evaluated. First, the associations through time between acetaminophen use and the prevalence of neurodevelopmental disorders are considered. A systematic review reveals that the use of acetaminophen in the pediatric population was never tracked carefully, but historical events that affected use of the drug were documented and are sufficient to establish apparent correlations with changes in the prevalence of neurodevelopmental disorders. Second, problems with exclusive reliance on results from meta-analyses of large datasets and from studies involving small time frames of drug exposure are reviewed. Third, the potential bias in a study designed to separate the role of vaccines and acetaminophen in the induction of autism spectrum disorder (Autism 2008;12:293-307) is carefully evaluated. Finally, evidence demonstrating why some children are susceptible to acetaminophen-induced neurodevelopmental injury is examined. It is concluded that, at least among the factors considered, there is no valid rationale for controversy regarding the conclusion that early life exposure to acetaminophen causes neurodevelopmental injury in susceptible babies and small children.
REVIEW | doi:10.20944/preprints202212.0215.v1
Subject: Medicine And Pharmacology, Psychiatry And Mental Health Keywords: ADHD; micronutrients; neurodevelopment; disattention; hyperactivity
Online: 13 December 2022 (01:58:34 CET)
Attention Deficit Hyperactivity Disorder is a neurodevelopmental disorder characterised by core symptoms of impulsivity, locomotor hyperactivity, and inattention affecting around 5% of children and adolescents worldwide. Although this brain illness is wrongly considered a childhood disorder, increasing evidences suggest that it can persist into adulthood in about 65% of cases leading to significant clinical, socio-relational, and occupational disabilities. Pharmacological and non-pharmacological treatments currently available permit to achieve numerous benefits, in particular, if started early in childhood, however, quality of life of patients affected by ADHD could be compromised in any case in terms of self-esteem, ability to finalize projects, and personal satisfaction. In this study we evaluated the impact of micronutrient formulations on ADHD symptoms in both children and adults analyzing results of randomized, placebo-controlled trials.
REVIEW | doi:10.20944/preprints202202.0115.v1
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: acetaminophen; autism; infant; paracetamol; neurodevelopment
Online: 8 February 2022 (13:42:48 CET)
Acetaminophen use during pregnancy and early childhood was accepted in the 1970s, but is now a subject of considerable concern. Careful analysis shows that initial acceptance of the drug was based on false assumptions and ignorance of the impact of the drug on brain development. Fourteen studies now indicate that prenatal exposure to acetaminophen is associated with neurodevelopmental problems. Based on corrections for confounding factors applied to the analyses of available data, it can be concluded that prenatal exposure to acetaminophen causes statistically significant risks of one subtype of autism spectrum disorder (ASD), developmental delays, and attention deficit hyperactivity disorder. In contrast, data regarding postnatal exposure to acetaminophen are limited, and several factors impede a classic multivariate analysis of data to resolve the issue. However, circumstantial evidence regarding postnatal exposure to the drug is abundant, and it can be concluded beyond a reasonable doubt that postnatal exposure to acetaminophen in susceptible children is responsible for many if not most cases of ASD. Circumstantial evidence includes at least three otherwise unexplained temporal relationships, data from laboratory animal studies, several miscellaneous and otherwise unexplained correlations, and the lack of alternative suspects that fit the evidence-derived profile.
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: behavior; neurodevelopment; infant; child; autism
Online: 19 October 2021 (10:13:55 CEST)
Background: Although widely believed to be safe for use in infants and children when used as directed, increasing evidence indicates that early life exposure to paracetamol (acetaminophen) may cause long-term neurodevelopmental problems. Further, recent studies in animal models demonstrate that cognitive development is exquisitely sensitive to paracetamol exposure during early development. In this study, evidence for the claim that paracetamol is safe was evaluated using a systematic literature search. Methods: Publications on PubMed between 1974 and 2017 that contained the keywords “infant” and either “paracetamol” or “acetaminophen” were considered. Of those initial 3096 papers, 218 were identified that made claims that paracetamol was safe for use with infants or children. From these 218, a total of 103 papers were identified as sources of authority for the safety claim. Results and Conclusions: A total of 52 papers contained actual experiments designed to test safety, and had a median follow-up time of 48 hours. None monitored neurodevelopment. Further, no trial considered total exposure to drug since birth, eliminating the possibility that the effects of drug exposure on long-term neurodevelopment could be accurately assessed. On the other hand, abundant and sufficient evidence was found to conclude that paracetamol does not induce acute liver damage in babies or children when used as directed.
ARTICLE | doi:10.20944/preprints201806.0083.v1
Subject: Medicine And Pharmacology, Anesthesiology And Pain Medicine Keywords: anesthesia; neurotoxicity; synapse; mTOR; neurodevelopment
Online: 6 June 2018 (10:36:51 CEST)
Human epidemiologic studies and laboratory investigations in animal models suggest that exposure to general anesthetic agents (GAs) have harmful effects on brain development. The mechanism underlying this putative iatrogenic condition is not clear and there are currently no accepted strategies for prophylaxis or treatment. Recent evidence suggests that anesthetics might cause persistent deficits in synaptogenesis by disrupting key events in neurodevelopment. Using an in vitro model consisting of dissociated primary cultured mouse neurons we demonstrate abnormal pre- and post-synaptic marker expression after a clinically relevant isoflurane anesthesia exposure conducted during neuron development. We find that pharmacologic inhibition of the mechanistic target of rapamycin (mTOR) pathway can reverse the observed changes. Isoflurane exposure increases expression of phospho-S6, a marker of mTOR pathway activity, in a concentration-dependent fashion and this effect occurs throughout neuronal development. The mTOR 1 complex (mTORC1) and the mTOR 2 complex (mTORC2) branches of the pathway are both activated by isoflurane exposure and this is reversible with branch-specific inhibitors. Upregulation of mTOR is also seen with sevoflurane and propofol exposure, suggesting that this mechanism of developmental anesthetic neurotoxicity may occur with all the commonly used GAs in pediatric practice. We conclude that GAs disrupt the development of neurons during development by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition.
REVIEW | doi:10.20944/preprints202305.0890.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: BOLD Signal Variability; Pediatrics; Biomarker; fMRI; Neurodevelopment
Online: 12 May 2023 (05:16:11 CEST)
Background: As pediatric BOLD SV is relatively novel, there is a need to provide a foundational framework that gives researchers an entry point into engaging with the topic. This begins with clarifying the definition of BOLD variability by identifying and categorizing the various metrics utilized to measure BOLD SV; Methods: A systematic review of the literature was conducted. Inclusion criteria were restricted to studies utilizing any metric of BOLD signal variability (BOLD SV) and with individuals younger than 18 in the study population. The definition of BOLD SV was any measure of intra-individual variability in the BOLD signal. Five databases were searched: Psychinfo, Healthstar, Medline, Embase, and Scopus; Results: Seventeen observational studies, including male (n =1796) and female (n =1324) pediatric participants were included. Eight studies quantified variability as the amount of deviation from average BOLD signal, 7 used complexity-based metrics, 3 used correlation measures of variability, and 1 used structure of the hemodynamic response function. Ten methods of quantifying signal variability were identified. Associations and trends in BOLD SV were commonly found with age, factors specific to mental and/or neurological disorders like attention deficit disorder, epilepsy, psychotic symptoms, and performance on psychological and behavioral tasks. Conclusions: BOLD SV is a potential biomarker of neurodevelopmental and neurological conditions and symptom severity in mental disorders for defined pediatric populations. Studies that establish clinical trends and identify the mechanisms underlying BOLD SV with a low risk of bias are needed before clinical applications can be utilized by physicians
ARTICLE | doi:10.20944/preprints202211.0512.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Thyroid hormones; Mixture; Neurodevelopment; Xenopus laevis; EDC
Online: 28 November 2022 (10:44:37 CET)
Thyroid hormones (THs) are essential for normal brain development, influencing neural cell differentiation, migration, and synaptogenesis. Multiple endocrine-disrupting chemicals (EDCs) are found in the environment, raising concern for their potential effects on thyroid hormone signaling and the consequences on neurodevelopment and behavior. While most research on EDCs investigates the effects of individual chemicals, human health may be adversely affected by a mixture of chemicals. Many compounds belonging to a wide range of chemical classes have been identified as EDCs, notably those affecting thyroid hormone signaling. We hypothesized that embryonic exposure to a mixture of chemicals (containing phenols, phthalates, pesticides, heavy metals, perfluorinated -, polychlorinated, and polybrominated compound) commonly found in the human amniotic fluid could lead to altered brain development to assess its effect on thyroid hormone signaling and neurodevelopment in an amphibian model (Xenopus laevis), highly sensitive to thyroid disruption. Newly hatched tadpoles were exposed for eight days to either TH (thyroxine, T4 10nM) or the amniotic mixture (1x concentration) and gene expression was analyzed in the brains of exposed tadpoles using both RT-qPCR and RNA sequencing. Results indicate that whilst some overlap on TH-dependent genes exist, T4 and the mixture have different gene signatures. Immunohistochemistry showed increased proliferation in the brains of T4-treated animals whereas no difference was observed for the amniotic mixture. Further, we demonstrated diminished tadpoles’ motility in response to T4 and mixture exposure. As the individual chemicals composing the mixture are considered safe, these results highlight the importance of examining the effects of mixtures to improve risk assessment
ARTICLE | doi:10.20944/preprints201810.0284.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: Autism; polychlorinated biphenyls; environmental chemicals; children; neurodevelopment
Online: 15 October 2018 (06:23:08 CEST)
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social communication and repetitive or stereotypic behaviours. In utero exposure to environmental chemicals, such as polychlorinated biphenyls (PCBs), may play a role in the etiology of ASD. We examined the relation between plasma PCB concentrations measured during pregnancy and autistic behaviours in a subset of children aged 3–4 years old in the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pregnancy and birth cohort of 546 mother-infant pairs from Canada (enrolled: 2008-2011). We quantified the concentrations of 6 PCB congeners that were detected in >40% of plasma samples collected during the 1st trimester. At age 3–4 years, caregivers completed the Social Responsiveness Scale-2 (SRS), a valid and reliable measure of children’s reciprocal social and repetitive behaviors and restricted interests. We examined SRS scores as both a continuous and binary outcome, and we calculated Bayesian predictive odds ratios for more autistic behaviours based on a latent variable model for SRS scores >60. We found no association between plasma PCB concentrations and autistic behavior, However, we found small and imprecise increases in the mean SRS score and odds of more autistic behaviour for the highest quartile of plasma PCB concentrations compared with the lowest quartile; for instance, an average increase of 1.1 [95%PCI: −0.5, 2.6] in the mean SRS (exposure contrast 4th versus 1st quartile) for PCB138 translated to an odds ratio of 1.6 [95%PCI: 1.0, 2.5]. Our findings illustrate the importance of measuring associations between PCBs and autistic behaviour on both continuous and binary scales.
ARTICLE | doi:10.20944/preprints202304.0408.v1
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: primitive reflexes; craniosacral dysfunction; neurodevelopment; early diagnosis; screening
Online: 17 April 2023 (05:32:57 CEST)
Background: In healthy children, the frequency of anomalous persistence of primitive reflexes (PRs) and craniosacral blocks (CBs) are unknown, as well as their impact on neurodevelopment, behaviour disorders and related consequences. We aim to know the prevalence of anomalous PRs and CBs in apparently healthy children and its relationships with behavior and neurodevelopment anomalies. Methods: Participants (n=120) were evaluated through physical examination to detect PRs and CBs, an ad hoc parent survey to collect perinatal events, and children behavior assessment by teachers using Battelle score. Results: PRs were present in 89.5%. Moro (70.8%), cervical asymmetric (78.3%) and cervical symmetric PRs (67.5%) were the most frequent observed PRs. CBs were found in 83.2%, and the most frequent CBs were dura mater (77.5%) and sphenoid bone (70%) blocks. Moro, cervical asymmetric and cervical symmetric active primitive reflexes are significantly associated to cranial blocks of dura mater, parietal zones, and sphenoid bone sway. Gestational disorders or perinatal complications were associated to a higher frequency of PRs and CBs. The presence of PRs and CBs were associated with abnormal Battelle scores and neurobehavioral problems. Conclusion: Presence of PRs and CBs in children without diagnosed diseases are frequent and related with disturbances in childhood neurodevelopment.
REVIEW | doi:10.20944/preprints202212.0205.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: prenatal alcohol consumption; gut microbiome; neurodevelopment; FASD; mice
Online: 12 December 2022 (13:50:01 CET)
Disorders associated with substance abuse are a major public health crisis with few treatment options. According to World Health Organization (WHO) ethanol is the most widely used drug in the world, and it represents a risk factor for the advent of disease, disability, and eventually death. Foetal Alcoholic Spectrum Disorders (FASD) is a diagnostic term to describe the range of effects that can occur in an individual whose mother drank alcohol during pregnancy. These effects encompass both physical, mental, behavioural and further lifelong disabilities. Besides, ethanol can harm the gut microbiota. Gut microbiome is firstly acquired from the mother and it is crucial for intestinal homeostasis during hosts’ lifetime. It is responsible for producing metabolites that benefits and protects the host from harm microbial colonization. Knowledge about the interactions between human gut microbes and the developing nervous system is still scarce. Nevertheless, animal models have shown that gut bacteria and microbial metabolites are strongly associated with Central Nervous System (CNS) homeostasis. Endotoxins such as Lipopolysaccharides (LPS) are hypothesized to have a major role in neurodegeneration, however, conclusions must be taken with care due to differences in sensitivity between humans and mice. In this review we focus on the role of gut microbiota on the neurodevelopment of mice when ethanol consumption is one of the major stressors during prenatal period. We detail the range of the endotoxin hypothesis in describing endotoxins’ contribution to neurodegeneration and the influence that kynurenine pathway has on the process.
REVIEW | doi:10.20944/preprints202104.0457.v1
Subject: Social Sciences, Psychology Keywords: perinatal; maternal; brain development; neurodevelopment; magnetic resonance imaging
Online: 19 April 2021 (09:02:39 CEST)
Brain development during the prenatal period is rapid and unparalleled by any other time during development. Biological systems undergoing rapid development are at higher risk for disorganizing influences. Therefore, certain prenatal exposures impact brain development, increasing risk for negative neurodevelopmental outcome. While prenatal exposures have been associated with cognitive and behavioral outcomes later in life, the underlying macroscopic brain pathways remain unclear. Here, we review studies investigating the association between prenatal exposures and infant brain development focusing on prenatal exposures via maternal physical health factors, maternal mental health factors, and maternal drug and medication use. Further, we discuss the need for studies to consider multiple prenatal exposures in parallel and suggest future directions for this body of research.
ARTICLE | doi:10.20944/preprints201911.0292.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: NHEJ; double-strand breaks; mouse model; lymphocyte; neurodevelopment
Online: 24 November 2019 (15:57:38 CET)
Classical non-homologous end joining (NHEJ) is a molecular pathway that detects, processes and ligates DNA double-strand breaks (DSBs) throughout the cell cycle. Mutations in several NHEJ genes result in neurological abnormalities and immunodeficiency both in humans and mice. The NHEJ pathway is required for the V(D)J recombination in developing B and T lymphocytes, and for class switch recombination in mature B cells. Ku heterodimer formed by Ku70 and Ku80 recognizes DSBs and facilitates the recruitment of accessory factors (e.g., DNA-PKcs, Artemis, Paxx and Mri/Cyren) and downstream core factors subunits XLF, XRCC4 and Lig4. Accessory factors might be dispensable for the process depending on the genetic background and DNA lesion type. To determine the physiological role of Mri in DNA repair and development, we introduced frame-shift mutation in the Mri gene in mice. We then analyzed the development of Mri-deficient mice as well as wild type and immunodeficient controls. Mice lacking Mri possessed reduced levels of class switch recombination in B lymphocytes and slow proliferation of neuronal progenitors when compared to wild type littermates. Human cell lines lacking Mri were as sensitive to DSBs as WT controls. Overall, we concluded that Mri/Cyren is largely dispensable for DNA repair and mouse development.
REVIEW | doi:10.20944/preprints202102.0030.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: AEA; 2-AG; CB1; CB2; endocannabinoid; regeneration; neurodevelopment; invertebrate
Online: 1 February 2021 (13:16:51 CET)
Cannabis has long been used for its medicinal and psychoactive properties. With the relatively new adoption of formal medicinal cannabis regulations worldwide, the study of cannabinoids, both endogenous and exogenous, has similarly flourished in more recent decades. In particular, research investigating the role of cannabinoids in regeneration and neurodevelopment has yielded promising results in vertebrate models. However, regeneration-competent vertebrates are few, whereas a myriad of invertebrate species have been established as superb models for regeneration. As such, this review aims to provide a comprehensive summary of the endocannabinoid system, with a focus on current advances in the area of endocannabinoid system contributions to invertebrate neurodevelopment and regeneration.
ARTICLE | doi:10.20944/preprints201811.0467.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: DISC1, neurodevelopment, synapse, CRMP-2, MUNC18, syntaxin, NECAP1, proteomics
Online: 19 November 2018 (12:25:42 CET)
A balanced chromosomal translocation disrupting DISC1 (Disrupted in Schizophrenia 1) gene has been linked to psychiatric diseases, such as major depression, bipolar disorder and schizophrenia. Since the discovery of this translocation, many studies have focused on understating the role of the truncated isoform of DISC1, hypothesizing that the gain of function of this protein could be behind the neurobiology of mental conditions, but not so many studies have focused in the mechanisms impaired due to its loss of function. For that reason, we perform an analysis on the cellular proteome of primary neurons in which DISC1 was knocked down with the goal of identifying relevant pathways directly affected by DISC1 loss of function. Using an unbiased proteomic approach, we found that the expression of 31 proteins related to neurodevelopment (e.g. CRMP-2, stathmin) and synaptic function (e.g. MUNC-18, NCS-1) is regulated by DISC1 in primary mouse neurons. Hence, this study reinforces the idea that DISC1 is a unifying regulator of both neurodevelopment and synaptic function, thereby providing a link between these two key anatomical and cellular circuitries.
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: Neural Stem Cell; Secretome; Neurodevelopment; Radial Glia; Neural Progenitor Cell
Online: 4 October 2021 (12:25:30 CEST)
Neural stem cell (NSC) based therapies are at the forefront of regenerative medicine strategies to combat illness and injury of the central nervous system (CNS). In addition to their ability to produce new cells, NSCs secrete a variety of products, known as the NSC secretome, that have been shown to ameliorate CNS disease pathology and promote recovery. As pre-clinical and clinical research to harness the NSC secretome for therapeutic purposes advances, a more thorough understanding of the endogenous NSC secretome can provide useful insight into the functional capabilities of NSCs. In this review, we focus on research investigating the autocrine and paracrine functions of the endogenous NSC secretome across life. We also compare the NSC secretome across species, finding signs of conserved parallels between rodent, human and zebrafish NSC secretomes. Throughout development and adulthood, we find evidence that the NSC secretome is a critical component of how endogenous NSCs regulate themselves and their niche. We also find gaps in current literature, most notably in the clinically relevant domain of endogenous NSC paracrine function in the injured CNS. Future investigations to further define the endogenous NSC secretome and its role in CNS tissue regulation are necessary to bolster our understanding of NSC-niche interactions and to aid in the generation of safe and effective NSC-based therapies.
REVIEW | doi:10.20944/preprints202012.0415.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: nutrition; brain; neurodevelopment; childhood; gut-brain axis; psychobiotics; macronutrients, micronutrients.
Online: 16 December 2020 (13:52:17 CET)
Proper nutrition is crucial for normal brain and neurocognitive development. Failure to optimize neurodevelopment early in life can have profound long-term implications for both mental health and quality of life. Although the first 1000 days of life represent the most critical period of neurodevelopment, the central and peripheral nervous systems continue to develop and change throughout life. All this time, development and functioning depend on many factors, including adequate nutrition. In this review, we outline the role of nutrients in cognitive, emotional, and neural development in infants and young children with special attention to the emerging roles of polar lipids and high quality (available) protein. Furthermore, we discuss the dynamic nature of the gut-brain axis and the importance of microbial diversity in relation to a variety of outcomes, including brain maturation/function and behavior are discussed. Finally, the promising therapeutic potential of psychobiotics to modify gut microbial ecology in order to improve mental well-being is presented. Here we show that the individual contribution of nutrients, their interaction with other micro-and macronutrients, and the way in which they are organized in the food matrix are of crucial importance for normal neurocognitive development.
COMMUNICATION | doi:10.20944/preprints202312.0513.v1
Subject: Neuroscience And Neurology, Biology And Life Sciences Keywords: TAU; MAPT; neurodevelopment; neurogenetic and neurodegenerative disease; isoform; disease mechanism; dementia
Online: 7 December 2023 (14:56:39 CET)
TAU is the main disease driver in Alzheimer’s and many other sporadic and genetic tauopathies. TAU is differently spliced, the role of individual splice-isoforms unclear. Murine Mapt-KO mice are healthy, and protected from Alzheimer’s, but no such case has been reported in humans. Using gnomad database, we here demonstrate that the only isoform expressed during fetal human brain development is intolerant to mutation, while other brain and peripheral nervous system TAU isoforms are dispensable. With TAU targeted therapies for Alzheimer’s and other tauopathies on the rise, we caution that TAU is essential human brain development.
REVIEW | doi:10.20944/preprints202304.0170.v1
Subject: Medicine And Pharmacology, Psychiatry And Mental Health Keywords: Neuromodulation; Brain Stimulation; Transcranial Direct Current Stimulation; Neurodevelopment Disorder; ADHD; ADD
Online: 10 April 2023 (10:39:24 CEST)
ADHD, a neurodevelopmental condition, is distinguished by a triad of symptoms including inattention, hyperactivity, and impulsivity. It is frequently accompanied by comorbidities such as anxiety, depression, and learning disabilities. As a result, clinicians often face challenges in accurately diagnosing ADHD and differentiating it from other conditions. As a prospective remedy for ADHD, scientists have investigated Transcranial Direct Current Stimulation (tDCS), a non-invasive technique of stimulating the brain. It involves applying low-intensity electrical currents to specific regions of the brain to modulate neural activity. This review paper aims to provide an overview of the comorbidities associated with ADHD and the differential diagnosis of the condition. It also explores the potential of tDCS as a treatment option for ADHD, including its mechanisms of action and efficacy in improving ADHD symptoms. The comorbidities discussed in this review include anxiety disorders, mood disorders, and substance use disorders. These comorbidities are frequently seen in individuals with ADHD and can complicate the diagnosis and treatment of the condition. The paper also highlights the importance of considering comorbidities when assessing ADHD, as well as the potential impact of these conditions on treatment outcomes. The differential diagnosis section of the paper explores conditions that can present with symptoms similar to ADHD, such as anxiety disorders, mood disorders, and learning disabilities. It emphasizes the need for a thorough assessment and differential diagnosis to identify ADHD and differentiate it from other conditions accurately. The final section of the paper discusses the potential of tDCS as a treatment option for ADHD. It examines the mechanisms of action of tDCS and its efficacy in improving ADHD symptoms, including attention, hyperactivity, and impulsivity. It also explores the potential for tDCS to improve comorbid conditions associated with ADHD. Overall, this review provides a comprehensive overview of comorbidities and differential diagnoses in ADHD and the potential of tDCS as a treatment option. The paper highlights the importance of a thorough assessment and personalized treatment plan for individuals with ADHD, particularly those with comorbidities.
REVIEW | doi:10.20944/preprints202109.0109.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: proteomics; transcriptomics; DNA methylation; mitochondria; metabolism; OXPHOS; ASD; neurogenesis; gliosis; neurodevelopment
Online: 6 September 2021 (17:14:37 CEST)
Abstract: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with extensive genetic and aetiological heterogeneity. While the underlying molecular mechanisms involved remain unclear, significant progress has been facilitated by recent advances in high-throughput transcriptomic, epigenomic and proteomic technologies. Here, we review recently published ASD proteomic data and compare proteomic func-tional enrichment signatures to those of transcriptomic and epigenomic data. We iden-tify canonical pathways that are consistently implicated in ASD molecular data and find an enrichment of pathways involved in mitochondrial metabolism and neurogenesis. We identify a subset of differentially expressed proteins that are supported by ASD tran-scriptomic and DNA methylation data. Furthermore, these differentially expressed proteins are enriched for disease phenotype pathways associated with ASD aetiology. These proteins converge on protein-protein interaction networks that regulate cell pro-liferation and differentiation, metabolism and inflammation which demonstrates a link between canonical pathways, biological processes and the ASD phenotype. This review highlights how proteomics can uncover potential molecular mechanisms to explain a link between mitochondrial dysfunction and neurodevelopmental pathology.
ARTICLE | doi:10.20944/preprints202309.0162.v1
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: extreme prematurity; surfactant; outcome; children; longitudinal study; pulmonary function testing; neurodevelopment; asthma
Online: 5 September 2023 (05:08:28 CEST)
This study aimed evaluating 7 years’ outcome in 118 very preterm newborn (VPN, gestational age=26±1.4wks) involved in a randomized controlled trial. They presented neonatal respiratory distress (RDS) requiring ventilation for 14±2 days post-natal age (PNA). Repeated instillation of 200mg/kg Poractant alfa (SURF) did not improve early bronchopulmonary dysplasia, but SURF infants needed less re-hospitalization than controls for respiratory problem at 1- and 2-years PNA. There was no growth difference at 7.1±0.3 years for 41 SURF vs. 36 controls (80% eligible children); 7.9% SURF vs. 28.6% controls presented asthma (p=0.021). Children underwent cogni-tive assessment (WISC IV) and pulmonary function testing (PFT) measuring spirometry, lung volumes and airway resistance. Spirometry showed differences (p<0.05) between SURF and con-trols (mean±standard deviation (median z-score)) for FEV1 (L/s) (1.188±0.690(-0.803) vs. 1.080±0.243(-1.446)); FEV1 after betamimetics (1.244±0.183(-0.525) vs. 1.091±0.209(-1.342)); FVC (L) (1.402±0.217 (-0.406) vs. 1.265±0.267(-1.141)), and FVC after betamimetics 1.452±0.237 (-0.241) vs. 1.279±0.264(-1.020)). PFT showed no difference in volumes or airway resistance. Global IQ median [Inter-quartile Range] was 89[82:99] vs. 89[76:98] with 61% children >85 in both groups. Former VPN presenting severe neonatal RDS treated with repeated Surfactant have improved lung function and less asthma at 7 years PNA. There were no differences in neurodevelopmental outcome
ARTICLE | doi:10.20944/preprints201810.0228.v1
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: cerebellar hemorrhage; intraventricular hemorrhage; preterm; MRI; neurodevelopment; outcome prediction; white matter injury
Online: 11 October 2018 (04:21:24 CEST)
Although the most common forms of brain injury in preterm infants have been associated with adverse neurodevelopmental outcomes, existing MRI scoring systems lack specificity, do not incorporate clinical factors, and are technically challenging to perform. The objective of this study was to develop a web-based, clinically-focused prediction system which differentiates severe from normal-moderate neurodevelopmental outcomes at two years. Infants were retrospectively identified as those who were born ≤30 weeks gestation, had MR imaging at term-equivalent age, and neurodevelopmental testing at 18-24 months. Each MRI was scored on injury in three domains (intraventricular hemorrhage, white matter injury, and cerebellar hemorrhage) and clinical factors strongly predictive of outcome were investigated. A binary logistic regression model was then generated from the composite of clinical and imaging components. A total of 154 infants were included (mean GA = 26.1±1.8 weeks, BW = 889.1±226.2 grams). The final model (imaging score + ventilator days + delivery mode + antenatal steroids + ROP requiring surgery) had strong discriminatory power for severe disability (AUC=0.850), with a PPV of 76% and NPV of 90%. Available as a web-based tool, it can be useful for prognostication and targeting early intervention services to infants who may benefit most from such services.
REVIEW | doi:10.20944/preprints202106.0637.v1
Subject: Social Sciences, Psychology Keywords: language; autism; development; perception; veridical mapping; autistic interests; deep phenotypes; clusters/subtypes; neurodevelopment
Online: 28 June 2021 (10:33:38 CEST)
What does the way autistics bypass, learn, and eventually master language tell us about humans’ genetically encoded linguistic ability? In this theoretical review, we argue that autistic non-social acquisition of language, as well as autistic savant abilities, provide a strong argument for an innate, human-specific orientation toward (and mastery of) complex embedded structures. Autistic non-social language learning may represent a widening of the material processed during development beyond oral language. Structure detection and manipulation and generative production of non-linguistic embedded and chained material (savant abilities in calendar calculation, musical composition and interpretation, three-dimensional drawing) may thus represent an application of such innate mechanisms to non-standard materials. Typical language learning through exposure to the child’s mother tongue may represent but one of many possible achievements of the same capacity. The deviation from typical language development in autism may ultimately allow access to oral language, sometimes in its most elaborate forms, but also explains the possibility of the absence of its development when applied exclusively to non-linguistic structured material. Such an extension of human capacities beyond, or in parallel to, their usual limits call into question what we consider to be specific or expected in humans and, therefore, does not necessarily represent a genetic “error”. Regardless of the adaptive success or failure of non-social language learning, it is up to science and ethical principles to strive to maintain autism as a human potentiality to further foster our vision of a plural society.
REVIEW | doi:10.20944/preprints202104.0472.v1
Subject: Social Sciences, Psychology Keywords: language; autism; development; perception; veridical mapping; autistic interests; deep phenotypes; clusters/subtypes; neurodevelopment
Online: 19 April 2021 (12:12:20 CEST)
What does the way autistics bypass, learn, and eventually master language tell us about human linguistic ability? Here, we argue that non-social acquisition of language, in addition to representing a strong argument for nativist models of human language, may be encompassed within the human-specific orientation and mastery of complex embedded structures, of which language represents one realization. Non-social language learning could thus represent the extension of available linguistic, and non-linguistic material processed by human genetic constraints, allowing language acquisition. This deviation from typical developmental language acquisition may ultimately allow access to language, sometimes in its most elaborate forms, and also explains the possibility of the absence of its development when applied to primarily non-linguistic structured material. However, such enlargement of material-specificity does not cast doubts about its human nature. Regardless of the adaptive success or failure of non-social language learning, it is up to science, legal policies, and ethical principles to strive to maintain autism as a human potentiality to further foster our vision of a plural society.
REVIEW | doi:10.20944/preprints201907.0188.v1
Subject: Biology And Life Sciences, Toxicology Keywords: polybrominated diphenyl ethers; PBDE; neurodevelopment; epigenetics; DNA methylation; chromatin remodeling; environmental toxins; toxicity
Online: 16 July 2019 (07:25:37 CEST)
Disruption of epigenetic regulation by environmental toxins is an emerging point of focus for understanding the latter’s impact on human health. Polybrominated diphenyl ethers (PBDEs), one such toxin, are an environmentally pervasive class of brominated flame retardants that have been extensively used as coatings on a wide range of consumer products. Their environmental stability, propensity for bioaccumulation, and known links to adverse health effects have evoked extensive research to characterize underlying biological mechanisms of toxicity. Of particular concern is the growing body of evidence correlating human exposure levels to behavioral deficits related to neurodevelopmental disorders. The developing nervous system is particularly sensitive to influence by environmental signals, including dysregulation by toxins. Several major modes of actions have been identified, but a clear understanding of how observed effects relate to negative impacts on human health has not been established. Here we review the growing body of evidence for epigenetic disruptions induced by PBDEs, including DNA methylation, chromatin dynamics, and non-coding RNA expression while discussing potential relationship between PBDEs and neurodevelopmental disorders.
REVIEW | doi:10.20944/preprints202309.2093.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Unmetabolized folic acid (UMFA); folic acid; one-carbon cycle; Methylation; epigenetic; carcinogenesis; aging; neurodevelopment; embryogenesis; folate
Online: 29 September 2023 (10:39:29 CEST)
This review delves into the intricate relationship between folate (Vitamin B9) intake, especially its synthetic form, folic acid, and its implications on health and disease. While folate plays a pivotal role in the one-carbon cycle, essential for DNA synthesis, repair, and methylation, concerns arise from its excessive intake. The literature underscores potential deleterious effects, such as an increased risk of carcinogenesis, disturbances in DNA methylation, and impacts on embryogenesis, pregnancy outcomes, neurodevelopment, and disease risk. Notably, these consequences stretch beyond the immediate effects, potentially influencing future generations through epigenetic reprogramming. We probe into the molecular mechanisms underlying these effects, including accumulation of unmetabolized folic acid, Vitamin B12 dependent mechanisms, altered one carbon metabolism, altered methylation patterns, and interactions with critical receptors and signaling pathways. Furthermore, we emphasize differences in the effects and mechanisms mediated by folic acid compared to natural folate. Given the widespread folic acid supplementation, it is imperative to further research its optimal intake levels, and the molecular pathways impacted by its excessive intake, ensuring the health and well-being of the global population.
REVIEW | doi:10.20944/preprints202104.0665.v3
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: Arachidonic acid, 20:4n-6; Brain; Docosahexaenoic acid, 22:6n-3; Fetus; Maternal diet; Cognitive; Infants; Neurodevelopment; Neurogenesis
Online: 14 June 2021 (14:54:08 CEST)
During the last trimester of gestation and for the first 18 months after birth, both docosahexaenoic acid,22:6n-3 (DHA) and arachidonic acid,20:4n-6 (ARA) are preferentially deposited within the cerebral cortex at a rapid rate. Although, the structural and functional roles of DHA in brain development are well investigated, similar roles of ARA are not well documented. The mode of action of these two fatty acids and their derivatives at different structural-functional roles and their levels in the gene expression and signaling pathways of the brain have been continuously emanating. In addition to DHA, importance of ARA has been much discussed in recent years for fetal and postnatal brain development and the maternal supply of ARA and DHA. These fatty acids are also involved in various brain developmental processes; however, their mechanistic cross talks are not clearly known yet. This review describes the importance of ARA, in addition to DHA to support the optimal brain development and growth and functional roles in the brain.