Search Results (148)

Background/Objectives: Fetal Alcohol Spectrum Disorder (FASD) is a preventable neurodevelopmental condition associated with dysfunction of fronto-subcortical networks affecting attention, executive function, and behavioral regulation. Central auditory processing difficulties frequently persist despite preserved peripheral hearing, complicating clinical evaluation when behavioral testing is limited or unreliable, and objective markers that do not depend on behavioral cooperation are therefore needed. This exploratory observational case study investigated whether Frequency-Following Responses (FFRs) can capture measurable within-subject change in speech-evoked neural encoding in a pediatric patient with FASD. Methods: FFRs were recorded at two time points bracketing an eight-session period of non-invasive superficial neuromodulation (NESA^®) in an 8-year-old girl with FASD, using speech syllables (/da/, /ba/, /ga/) presented monaurally at 80 dB SPL. Two-tailed block-level Mann–Whitney U tests with rank-biserial correlations compared peak latencies, sustained pitch-tracking metrics (pitch strength, pitch error), onset stimulus–response correlation, and signal-to-noise ratio. Results: Sustained pitch-tracking metrics differed between time points, with increased pitch strength and reduced pitch error, whereas onset peak latencies, onset cross-correlation, and signal-to-noise ratio remained stable. Peak C, marking the transition to the sustained portion of the response, occurred earlier at the post-assessment in all six stimulus–ear combinations. The differences were therefore selective to sustained encoding rather than to onset timing or recording quality. Conclusions: FFR-derived pitch-encoding metrics detected measurable within-subject change, providing proof of concept for the feasibility of FFRs as a candidate objective tool for longitudinal monitoring of speech-evoked neural encoding in pediatric FASD. This single-case observation does not evaluate diagnostic accuracy, sensitivity, specificity, or discrimination from typically developing children, and therefore does not establish FFR as a validated diagnostic technique. The findings are hypothesis-generating and motivate controlled longitudinal studies. Full article

Prenatal alcohol exposure (PAE) leads to fetal alcohol spectrum disorder (FASD), the most common preventable cause of neurodevelopmental impairment. The classical narrative attributes the clinical picture of FASD exclusively to direct ethanol-induced brain injury. In the present review, we argue that this perspective is incomplete and leads to diagnostic errors, most often to the misdiagnosis of ADHD in children who in fact have FASD. We propose that, alongside the direct neurotoxicity of ethanol, an important and clinically under-recognized complementary mechanism is gut–brain axis dysfunction: alcohol damages the enteric nervous system and enteric glial cells, induces dysbiosis with deep deficits of butyrate and other short-chain fatty acids (SCFAs), damages the enterochromaffin cells responsible for 90% of peripheral serotonin production, and—through translocation of lipopolysaccharide (LPS) and activation of the Toll-like receptor 4 (TLR4)—sustains a neuroinflammatory brain signature. This cascade—superimposed on direct ethanol neurotoxicity—may account for the high rates of depression, anxiety, self-injurious behavior, and suicide attempts observed in individuals with FASD and for the limited efficacy of traditional interventions focused solely on the central nervous system. The 2024 Polish Institute of Mother and Child (Okulicz-Kozaryn et al.) study showed that 50.3% of pregnant women consumed alcohol, and 11% did so regularly, against only 7% who admitted so in questionnaires. The real clinical picture of children with FASD is further complicated by three factors to which we devote separate sections in this paper: prenatal co-exposure to nicotine, cannabinoids, and opioids; the loss of vertical microbiota transmission and breastfeeding in children transferred to foster care (where the prevalence of FASD is 18.8% and in children’s homes in some regions reaches up to 80%); and the substantial over-representation of preterm and small-for-gestational-age (SGA) infants (in the Hasken et al. cohort, 18.4% of children with FASD were born preterm and 51.4% were born SGA). In the final section, we present a structured, staged protocol for nutritional and microbiological intervention grounded in a hierarchy of evidence: from interventions supported by randomized controlled trials (RCT-level; choline) through interventions supported by strong mechanistic rationale and RCTs in related populations (sodium butyrate, Lactobacillus rhamnosus GG, GOS/FOS prebiotics—galacto-oligosaccharides and fructo-oligosaccharides, and omega-3 fatty acids) to experimental interventions. The protocol also covers the window before 2 years of age: we argue that, given the over-representation of preterm and SGA infants among children with FASD, the analogy to preterm infants on parenteral nutrition and to post-institutional infants applies in substantial part to the same patients, which justifies extending the indications for choline and other nutritional interventions. The paper includes a compact table of dosing proposals for each age window (from pregnancy to school-age child) and provides clinicians with concrete answers: where to start, what to avoid, and what to monitor, with explicit signposting of regulatory limitations for individual substances in Poland and the European Union. Full article

Alcohol exposure during pregnancy leads to fetal alcohol spectrum disorders (FASD), yet the mechanisms through which alcohol disrupts the developing cerebrovasculature remain poorly defined. Acetaldehyde, the first oxidative metabolite of alcohol, can alter vascular function, but whether developing cerebral arteries possess intrinsic capacity to generate acetaldehyde is unknown. Alcohol is primarily oxidized by alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and catalase (CAT), and their local metabolic activity may contribute to cerebrovascular vulnerability. In this study, cerebral arteries were isolated from postnatal day (PND) 10 C57BL/6J mouse offspring (third trimester-equivalent to human pregnancy), and incubated ex vivo with physiologically relevant alcohol concentrations (13 or 50 mM). Acetaldehyde generation, transcript expression, protein abundance, and catalase-dependent metabolism were evaluated. Alcohol exposure produced a concentration-dependent increase in acetaldehyde generation within developing cerebral arteries, with comparable responses between males and females. Transcript analysis revealed that Adh1, Cyp2e1, and Cat were expressed across developing tissues; however, Western blotting showed that catalase was the only alcohol-metabolizing enzyme detectable at the protein level within developing cerebral arteries. Accordingly, catalase inhibition by sodium azide altered acetaldehyde production, revealing a significant blocker–sex interaction at the higher inhibitor concentration (0.06 mM). In summary, our ex vivo findings demonstrate that developing cerebral arteries possess intrinsic metabolic capacity to oxidize alcohol to acetaldehyde and that catalase plays an essential role in supporting this process at this developmental stage. These results point to a previously unrecognized metabolic pathway within the developing cerebrovasculature that may potentially contribute to early-life vulnerability to alcohol exposure. Full article

Prenatal alcohol exposure (PAE) is recognized as a major public health concern due to its profound and lasting effects on the central nervous system (CNS) and its ability to induce fetal alcohol spectrum disorders (FASD), which encompass a wide range of cognitive, behavioural, and neuropsychiatric disorders that persist throughout life. Experimental and clinical studies have identified several mechanisms underlying ethanol impairing brain development, including apoptosis, oxidative stress, disruption of morphogen and growth factor signalling pathways, impaired neuronal proliferation and migration, neurotransmitter systems’ dysfunction, glial cells damage associated with deficient myelination, vascular and blood–brain barrier (BBB) alterations, and lasting epigenetic reprogramming. However, to date no widely accepted integrative framework explaining how these impairments underline the heterogeneous phenotype observed in FASD is available. The present brings together developmental neurobiology and computational neuroscience to conceptualize PAE as a disorder of emerging neural and functional architecture. Here, we summarize the pharmacokinetics of ethanol in pregnancy, critical windows of vulnerability, and the classical pathways of alcohol teratogenesis affecting neuronal survival, migration, synaptogenesis, myelination, and gene regulation. We have also reviewed MRI, diffusion imaging, and EEG/MEG evidence showing altered brain volumes, white matter microstructure, functional connectivity, and network organization in individuals with PAE. Finally, we propose a systems-level model that conceptualizes PAE as a disorder of emerging neuro-computational architecture, in which ethanol-induced cellular and molecular perturbations collectively alter the building blocks and self-organization rules of brain network assembly. Full article

Prenatal alcohol exposure (PAE) can cause fetal alcohol spectrum disorder (FASD). The FASD continuum encompasses facial dysmorphism, growth failure, and central nervous system (CNS) abnormalities/dysfunctions. Because some of these features may not be apparent in newborns, detecting PAE in the neonatal period is challenging, while early diagnosis may improve neurodevelopmental outcomes. Maternal self-reported alcohol consumption is limited by recall bias and denial, leading to misdiagnosis. Currently, there is a lack of universally implemented and standardized tools for identifying PAE/FASD in children across clinical settings. We aimed to review the existing literature on PAE assessment methods. Analysis of alcohol metabolites in neonatal meconium is the most widely studied and appears to be feasible for routine use, but it has some limitations. Recent advances in understanding the effects of alcohol on neurotransmitters, growth factors, and gene activity have contributed to the development of novel diagnostic strategies and have brought us closer to effective PAE detection. Some laboratory assays appear to be feasible for implementation in routine clinical practice, i.e., testing for pro- and anti-inflammatory cytokines, including interleukins (IL): IL-6, IL-1β, IL-10, and tumor necrosis factor-alpha (TNF-α) and Insulin-like Growth Factor 1(IGF1). These molecular approaches hold promise but require replication and validation before becoming the standard in clinical practice. Further research on biomarkers and other screening tools should continue to determine their feasibility and availability. Full article

Background: Fetal alcohol spectrum disorders (FASDs) are lifelong neurodevelopmental conditions resulting from prenatal alcohol exposure. Despite high FASD rates in high-risk adoptive populations, little is known about the experiences of adoptive parents in Israel, where underdiagnosis and limited professional awareness persist. Drawing on ecological and family systems theory, this study explored the daily challenges, coping strategies, and service-related barriers encountered by adoptive parents raising children with FASD. Methods: Using a qualitative, exploratory design, semi-structured interviews were conducted with 12 adoptive parents of children aged 9–18 years with a parent-reported clinical diagnosis of FASD made by a healthcare professional. The interviews focused on child-related difficulties, coping mechanisms, diagnostic experiences, and interactions with health, education, and welfare systems. The data were analysed using reflexive thematic analysis. Results: Five themes were identified: (a) child-related neurodevelopmental and behavioral challenges, (b) emotional and practical caregiving burden, (c) systemic barriers, including limited professional knowledge and fragmented diagnostic pathways, (d) coping strategies and family strengths, and (e) unmet needs and recommendations. Parents described fluctuating child functioning, chronic caregiving demands, and significant gaps in diagnostic and educational support. Conclusions: Adoptive parents raising children with FASD face substantial daily challenges compounded by systemic limitations. This study’s findings underscore the need for improved professional training, clearer diagnostic pathways, FASD-informed educational practices, and coordinated multidisciplinary services. These results provide direction for policy and service development to improve support for families affected by FASD. Full article

Fetal alcohol spectrum disorders (FASD) encompass a continuum of developmental abnormalities caused by prenatal alcohol exposure, resulting in persistent neurodevelopmental and structural defects. Accumulating evidence indicates that redox dysregulation plays a central role in the pathogenesis of FASD. Ethanol disrupts cellular redox homeostasis by promoting excessive reactive oxygen species production and depleting endogenous antioxidants, thereby perturbing key redox-sensitive molecular networks. Dysregulation of these pathways leads to mitochondrial dysfunction, endoplasmic reticulum stress, lysosome dysfunction, and disrupted cellular processes, including proliferation, differentiation, and migration, while also promoting apoptosis and neuroinflammation, ultimately leading to the developmental abnormalities characteristic of FASD. Recent studies demonstrate that antioxidant supplementation or targeted modulation of redox-sensitive signaling can mitigate these deleterious effects in preclinical models. This review synthesizes current knowledge of the molecular networks underlying redox dysregulation in FASD and discusses emerging antioxidant and dietary interventions with therapeutic potential. Elucidating these mechanisms provides critical insight into the pathogenesis of FASD and may inform the development of effective strategies for the prevention and treatment of FASD. Full article

Background/Objectives: Fetal alcohol spectrum disorders (FASDs) occur in nearly 5% of children in the United States and have been associated with alterations in neurological functions, neuroanatomical changes, and behavioral deficits encompassing an individual’s lifetime. Alterations in myelination have been reported in both rodent models and humans. The cerebellum is a heavily myelinated brain region, and oligodendrocyte and myelination transcripts have been reported to be altered in the cerebellum following early-life ethanol (EtOH) exposure in a mouse model. In this study, we investigated cerebellar-recruited behaviors in adult female mice that were exposed to EtOH from postnatal day (P) 4 to P9. We investigated whether changes in oligodendrocyte lineage markers were present in adulthood. Methods: C57BL/6J offspring received a total of 5.0 g/kg/day of either ethanol (EtOH) or saline in two separate doses delivered subcutaneously two hours apart from P4 to P9. On P21, offspring were weaned and housed with same-sex littermates throughout the duration of the study. From P60 to P90, females underwent behavioral testing including an open field test (OFT), rotarod, and balance beam. Behavior naïve littermates were euthanized on P105, and cerebella were collected for qPCR to assess oligodendrocyte lineage transcripts. Results: We reported that, following EtOH exposure from P4 to P9, adult female mice had increased ambulatory behaviors in the OFT and subtle changes in behavior in the rotarod and balance beam compared to saline-exposed controls. Despite the behavioral changes observed in adulthood, we found that alterations in oligodendrocyte lineage transcripts present on P10 did not persist into adulthood. Conclusions: Subcutaneous injection of EtOH from P4 to P9 resulted in long-term consequences in locomotor and cerebellar-recruited behaviors in female mice. Full article

Background/Objectives: Emerging evidence has suggested that choline is an effective treatment for at least some of the neurobehavioral deficits associated with Fetal Alcohol Spectrum Disorders (FASD). However, the mechanism of how choline works to ameliorate ethanol’s teratogenic effects, and whether it acts directly on the fetus or indirectly by altering the uterine environment, remains unknown. Previous work from our lab demonstrated that 4 BXD mouse strains that show high levels of ethanol-induced cell death on embryonic day 9.5 (E9.5) have differential responses to choline supplementation. This differential response in mouse strains highlights a need to further understand the role of genetics in choline metabolism. Because the liver is the central organ for choline metabolism, and the embryonic liver of mice is not functional this early in gestation, we focused on choline metabolism in the liver of the dam. Methods: Using a bioinformatics approach, the goals were to assess whether (1) genetic differences in liver choline metabolism in the dam could affect ethanol-induced cell death in a genotype-specific manner and (2) any of these candidate genes in the liver of the dam could be linked to differential response to choline amongst the strains. By performing a literature review, haplotype analysis among the 4 BXD strains, and liver protein expression analysis among 3 strains, we show that there are genetic differences in choline metabolic genes that are consistent with the hypothesis that maternal choline metabolism could mediate differential sensitivity. Results: While we identified two genes as promising candidates for the variable responses to choline supplementation among the four previously identified BXD strains choline/ethanolamine phosphotransferase 1 (cept1) and choline transporter gene solute carrier family 44 member 1 (slc44a1), the wealth of data on slc44a1 makes it the stronger candidate and suggests that it should be further explored. Conclusions: Genetic differences in maternal choline metabolism are present and may underlie variable therapeutic responses to choline, warranting a hypothesis that requires further investigation across animal models and human populations. Full article

The impairment of neural crest cells (NCCs) plays a pivotal role in the pathogenesis of fetal alcohol spectrum disorders (FASD). Epigenetic regulators mediate ethanol-induced disruptions in NCC development and represent promising targets for nutritional interventions. Here, we developed a biologically informed machine learning framework to predict nutritional supplements that modulate five key epigenetic regulators (miR-34a, DNMT3a, HDAC, miR-125b, and miR-135a) and mitigate ethanol’s adverse effects on NCCs. The optimized models demonstrated robust predictive performance and identified a number of nutritional supplements that could attenuate ethanol-induced NCC impairment, including resveratrol, vitamin B12, emodin, quercetin, and broccoli sprout-derived compounds. Our optimized models also revealed structural features that are critical for mitigating ethanol-induced NCC impairment through specific epigenetic mechanisms. These findings support predictive modeling as a tool to prioritize nutritional supplements for further investigation and the development of dietary strategies to prevent or reduce the risk of FASD. Full article

Alcohol (ethanol; EtOH) intake affects one in ten pregnancies in the United States and is a leading cause of developmental defects collectively known as fetal alcohol spectrum disorders (FASDs). Cerebral circulation is a critical target of prenatal ethanol exposure (PEE), yet the target(s) involved remain poorly understood. In adult cerebral circulation, mitochondrial function is essential in regulating smooth muscle contractility, suggesting mitochondria as a potential target of alcohol in the developing cerebral arteries. In this study, pregnant C57BL/6J mice were administered ethanol (3, 4.5, 6, or 7 g/kg) during either the second trimester equivalent of human pregnancy (gestational days 9–19), or the third trimester equivalent during postnatal days 1–10. Maternal and progeny blood ethanol concentrations, progeny brain weight, cerebral artery oxygen consumption, and corticosterone levels were measured. At lower ethanol concentrations (3 g and 4.5 g/kg), no significant alterations in fetal cerebral artery mitochondrial function were detected. In contrast, heavy maternal ethanol exposure (6 g/kg) significantly increased mitochondrial respiratory parameters in developing cerebral arteries during the third trimester equivalent of human pregnancy. Sex-specific dimorphism was also observed at this developmental stage. Corticosterone was not elevated in fetuses and pups. In summary, our findings demonstrate developmental stage- and sex-dependent vulnerabilities of cerebrovascular oxygen consumption to ethanol exposure. Full article

Background/Objectives: This article aims to investigate the multifaceted effects of alcohol on neurophysiopathological development from gestational stages through adult life and the consequent dynamic-relational challenges in individuals with Fetal Alcohol Spectrum Disorder (FASD). FASD, resulting from prenatal alcohol exposure (PAE), is characterized by a range of neurological, cognitive, behavioral, and sometimes physical impairments. This article explores how alcohol and its toxic metabolites cross the placenta, inducing direct cellular toxicity and epigenetic alterations that disrupt critical neurodevelopmental processes such as neurogenesis and brain circuit formation. Clinically, individuals with FASD exhibit diverse deficits in executive functioning, learning, memory, social skills, and sensory-motor abilities, leading to significant lifelong disabilities. A central focus is the application of the World Health Organization’s International Classification of Functioning, Disability and Health (ICF) criteria to comprehensively frame these disabilities. The ICF’s biopsychosocial model allows for a multidimensional assessment of impairments in body functions and structures, limitations in activities, and restrictions in participation, while also considering the crucial role of environmental factors. Methods: PubMed and Semantic Scholar databases were searched for relevant papers published in English. Results: This article highlights the utility of the ICF in creating individualized functioning profiles to guide interventions and support services, addressing the limitations of traditional assessment methods. Conclusions: While the ICF framework offers a robust approach for understanding and managing FASD, further research is essential to develop and validate FASD-specific ICF-based assessment tools to enhance support and social participation for affected individuals. Full article

Background/objectives: Alcohol use during pregnancy can result in adverse outcomes for the offspring, including Fetal Alcohol Spectrum Disorders (FASD). Psychosocial and contextual factors may influence gestational alcohol intake and women’s risk perception. This systematic review aimed to assess pregnant women’s and women of childbearing age’s perceived risk of alcohol use during pregnancy and to evaluate their knowledge of its potential effects on children. Methods: Following the PRISMA guidelines, a systematic search was conducted in Web of Science, PubMed and PsycArticles databases for studies published up to May 2025. Eligible studies examined gestational alcohol use, risk perception, or knowledge of fetal consequences among pregnant women or women of reproductive age. Methodological quality was assessed with the Critical Appraisal of Qualitative Studies tool from the Centre for Evidence-Based Medicine (CEBM). Results: Twenty-nine studies were included. Reported prevalence of alcohol consumption during pregnancy varied considerably across settings. A substantial proportion of women perceived alcohol use during pregnancy as acceptable, often depending on quantity, frequency, type of beverage, or stage of gestation. Knowledge of FASDs was generally limited and frequently restricted to physical malformations. Misconceptions were more common among women with prior alcohol use. The findings highlight persistent gaps in risk perception and knowledge about FASDs. Conclusions: Prevention strategies should not be limited to pregnant women but should also target women of childbearing age, especially those with active drinking patterns, as well as their immediate sociocultural environment. Strengthening professional training, community-based interventions, and consistent public health messaging are essential to reduce gestational alcohol exposure. Full article

Fetal alcohol spectrum disorder (FASD/FAS) is a chronic inflammatory process of the fetal brain induced by alcohol and mediated by pro-inflammatory (PILM) and pro-resolving (PRLM) lipid mediators of inflammation. DHA (docosahexaenoic acid) is an essential precursor of PRLM. A study examining the response of lipid mediators of inflammation to alcohol insult and DHA supplementation can provide vital information on the pathogenesis of FASD/FAS and the potential ameliorative role of DHA. Four groups of timed pregnant rats were studied: control, low-dose (1.6 g/kg/day) and high-dose (2.4 g/kg/day) alcohol, and high-dose alcohol (2.4 g/kg/day) + DHA (1250 mg/kg/day). The pups were delivered on day 20, and their whole brain was examined for lipid mediators by liquid chromatography mass spectroscopy. The following biomarkers of brain lipid mediators were studied, namely, PILM (LTB4, PGE2, PGF2α, TXB2) and PRLM (LXA5, 4-HDoHE, 17-HDoHE, and MaR1n-3, DPA). The brain PILM and PRLM concentrations decreased significantly (p < 0.001) with high-dose alcohol. However, high-dose alcohol + DHA resulted in a significant (p < 0.001) increase in PRLM levels, viz., LXA5, MaR1n-3 DPA, 17-HDoHE, and a threefold increase in 4-HDoHE. We conclude that DHA supplementation in alcohol-exposed pregnant rats significantly increased levels of brain pro-resolving lipid mediators in the offspring, suggesting a potential role in modulating the inflammatory response. Full article

Alcohol consumption during pregnancy and lactation remains a significant global issue. Preventive policies have proven insufficient, and consumption rates remain high, mainly due to a lack of awareness, the misconception that only high alcohol intake harms the fetus, inconsistent medical advice, and pre-existing alcohol use disorders. Alcohol consumption is linked to child harm during critical stages of development. Using a recently published model of fetal alcohol spectrum disorder (FASD) developed by our group, we analyzed brain changes in mothers who consumed alcohol during pregnancy and lactation and the behavioral consequences at the emotional-cognitive level and in caring for their offspring. We also considered the previous drinking history, using the paradigm of voluntary pre-gestational alcohol consumption. In addition, from gestational day 7 (GD7) until the day of sacrifice, mothers received a 3 g/kg dose of alcohol every 12 h via gavage. Our findings revealed deficiencies in maternal care, anxiety and depressive-like behavior, and aversive stimulus learning disturbances. These were associated with changes in gene targets linked to stress-axis regulation, reward circuits, and neuroplasticity. Additionally, we observed increased microgliosis and astrogliosis, indicating neuroinflammation in brain regions involved in cognition and emotional states’ regulation. Full article