Prenatal and Postnatal Choline Supplementation in Fetal Alcohol Spectrum Disorder.

Fetal alcohol spectrum disorder (FASD) is common and represents a significant public health burden, yet very few interventions have been tested in FASD. Cognitive deficits are core features of FASD, ranging from broad intellectual impairment to selective problems in attention, executive functioning, memory, visual-perceptual/motor skills, social cognition, and academics. One potential intervention for the cognitive impairments associated with FASD is the essential nutrient choline, which is known to have numerous direct effects on brain and cognition in both typical and atypical development. We provide a summary of the literature supporting the use of choline as a neurodevelopmental intervention in those affected by prenatal alcohol. We first discuss how alcohol interferes with normal brain development. We then provide a comprehensive overview of the nutrient choline and discuss its role in typical brain development and its application in the optimization of brain development following early insult. Next, we review the preclinical literature that provides evidence of choline's potential as an intervention following alcohol exposure. Then, we review a handful of existing human studies of choline supplementation in FASD. Lastly, we conclude with a review of practical considerations in choline supplementation, including dose, formulation, and feasibility in children.

Suggestibility and confabulation among individuals with Fetal Alcohol Spectrum Disorder: A review for criminal justice, forensic mental health, and legal interviewers.

Fetal Alcohol Spectrum Disorders (FASD) are conditions arising from prenatal alcohol exposure which results in a range of neurodevelopmental deficits in areas including cognition, memory, language, executive functioning, emotional regulation, and adaptive functioning. Deficits in various neurodevelopmental areas can range from mild to severe, depending on many factors including the quantity and timing of alcohol exposure during the prenatal development period. During interviews in criminal justice, forensic mental health, and legal contexts (e.g., criminal investigations, cross examination, victim interviews, interviews for lawsuits, forensic evaluations, pre-sentence investigations), deficits associated with FASD may elevate the risk of suggestibility and confabulation. These issues can result in negative jurisprudence-related outcomes, including impulsive Miranda rights waivers, incorrect assumptions of competency, inaccurate or incomplete information gathering, misinterpretation of intent, witness reliability issues, court ordered treatment completion problems, probation and parole violations, false confessions, and false accusations. The aim of the present article is to explain the context in which these issues can arise and provide criminal justice, forensic mental health, and legal professionals with key guidelines that can assist in minimizing suggestibility and confabulation when interviewing persons with FASD. We hope that the suggestions and strategies presented in this article will reduce potential obstructions of justice and enhance the quality of information obtained from individuals impacted by FASD. A brief discussion is also provided to identify additional research and training opportunities needed to clarify "best practices" for professionals tasked with evaluating the challenges facing this unique population.

GC-TOF-MS-Based Metabolomic Analysis and Evaluation of the Effects of HX106, a Nutraceutical, on ADHD-Like Symptoms in Prenatal Alcohol Exposed Mice.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that occurs in children characterized by inattention and hyperactivity. Prenatal alcohol exposure (PAE) can disrupt fetal neuronal development and cause an ADHD-like hyperactive behavior in the offspring. In this study, we hypothesized that metabolic disturbance would involve in ADHD neuropathology and aimed to investigate the changes in metabolite profile in PAE-induced ADHD-like model and the effects of HX106, a nutraceutical, on ADHD-like pathophysiology and metabolite changes. To this end, we administered HX106 to the mouse offspring affected by PAE (OPAE) and assessed the hyperactivity using the open field test. We observed that HX106-treated OPAE showed less hyperactive behavior than vehicle-treated OPAE. The effects of HX106 were found to be related to the regulation of dopamine transporter and D2 dopamine receptor expression. Furthermore, using gas chromatography time-of-flight mass spectrometry-based metabolomics, we explored the metabolite changes among the experimental groups. The metabolite profile, particularly related with the amino acids, linoleic acid and amino sugar pathways, was altered by PAE and reversed by HX106 treatment partially similar to that observed in the control group. Overall, this study suggest that metabolite alteration would be involved in ADHD pathology and that HX106 can be an efficient supplement to overcome ADHD by regulating dopamine signaling-related protein expression and metabolite changes.

Fetal alcohol spectrum disorders awareness in health professionals: implications for psychiatry.

Fetal Alcohol Spectrum Disorders (FASD) are a plethora of malformative conditions leading to mental retardation that affect newborns and children who have been exposed to alcohol during pregnancy or breastfeeding. FASD is a relevant topic for public health in Europe: European area is first in ranking for alcohol use during pregnancy with a prevalence of 25.2%. Italy ranked third among European countries with higher prevalence of FASD (45.0 per 1000 population). Furthermore, FASD could still be underestimated because of numerous undiagnosed and misdiagnosed cases. Aims of the study were to briefly summarize existing evidences about FASD and its psychiatric aspects to assess knowledge, attitudes and practice towards alcohol drinking during pregnancy in an Italian sample of health care professionals in order to provide information about FASD prevention. An anonymous online questionnaire containing the AUDIT-C, T-ACE model and the Drinking Motive Questionnaire was sent to 400 Italian healthcare professionals and students. The survey included socio-demographic information, questions about drinking habits and about knowledge, attitude and practice towards alcohol assumption during pregnancy. Among 320 respondents, 96.3% were women. AUDIT-C revealed that 52.4% were low risk drinkers but 27.6% were hazardous drinkers. The 90.6% of participants denied to ever attended a course about the fetus damage induced by alcohol consumption during pregnancy but 91.3% were willing to participate to professional update initiatives on the topic. Only 19.1% of participants talk regularly about the deleterious effects for the fetus of prenatal alcohol drinking to women and only 51.1% advise the 'zero alcohol' policy. Around 41% of participants tolerates the assumption of low-alcohol beverages. No differences were found between no drinkers and low and hazardous drinkers. In conclusion, data show that only specific and continuing updating for health care professionals about drinking habits may have impactful actions to prevent gestational alcohol intake in order to prevent the main cause of mental retardation in western countries.

Curcumin treatment attenuates alcohol-induced alterations in a mouse model of foetal alcohol spectrum disorders.

Alcohol exposure during development produces physical and mental abnormalities in the foetus that result in long-term molecular adjustments in the brain, which could underlie the neurobehavioural deficits observed in individuals suffering from foetal alcohol spectrum disorders. In this study, we assessed the effects of curcumin on cognitive impairments caused by prenatal and lactational alcohol exposure (PLAE). Furthermore, we examined whether curcumin could counteract the molecular alterations that may underlie these behavioural impairments. We focused on inflammatory and epigenetic mechanisms by analysing the expression of pro-inflammatory mediators, such as IL-6, TNF-α, and NF-κB, in the hippocampus and prefrontal cortex, as well as microglia and astrocyte activation in the dentate gyrus. We also assessed the activity of histone acetyltransferase in these brain areas. To model binge alcohol drinking, we exposed pregnant C57BL/6 mice to a 20% v/v alcohol solution during gestation and lactation, with limited access periods. We treated male offspring with curcumin during postnatal days (PD28-35) and then evaluated their behaviour in adulthood (PD60). Our results showed that curcumin treatment during the peri-adolescence period improved the anxiety and memory deficits observed in PLAE mice. At the molecular level, we found enhanced histone acetyltransferase activity in mice subjected to PLAE that curcumin treatment could not reverse to baseline levels. These mice also showed increased expression of pro-inflammatory mediators, which could be rescued by curcumin treatment. They also displayed astrogliosis and microglia activation. Our study provides further evidence to support the use of curcumin as a therapeutic agent for counteracting behavioural and molecular alterations induced by PLAE.

Hyperlocomotion and anxiety- like behavior induced by binge ethanol exposure in rat neonates. Possible ameliorative effects of Omega 3.

Maternal alcohol consumption during pregnancy may cause neurocognitive and behavioral disorders that can persist until adulthood. Epidemiological data has revealed an alarming increase in the frequency of alcohol intake in pregnant women. Nutritional variables may also have an impact on the behavioral alterations occasioned by alcohol during development. Moreover, omega-3, a polyunsaturated fatty acid necessary for normal brain development, is deficient in ethanol-treated animals. Although studies have shown that omega-3 supplementation after prenatal ethanol (EtOH) treatment improves some disorders, there are no reports about acute treatment with omega-3 in binge alcohol neurotoxic models during postnatal development. The goal of this study was to determine whether an administration of omega-3, after an acute ethanol dose in neonates, would be able to attenuate alcohol effects in offspring. Male/ female rats were administered ethanol (2.5 g/kg s.c. at 0 and 2 h) or saline on postnatal day (PND) 7, with a single dose of omega-3 (720 mg/kg) 15 min after the last alcohol injection. It was have found that EtOH-treated animals showed hyperlocomotion on PND 14 (pre-juvenile), and anxiety-like behavior was observed at all the three ages studied. Administration of omega-3 after EtOH treatment reduced hyperlocomotion and the anxiety-like behaviors on PND 14, but did not diminish the anxiety on either PND 20 or 30 (juvenile). In conclusion, acute ethanol exposure produced neurobehavioral alterations that persisted in the offspring, with omega-3 able to ameliorate these effects on PND 14. These data are relevant considering that omega-3 administration may have therapeutic effects through mitigating some of ethanol´s damaging consequences.

Feasibility and Acceptability of Maternal Choline Supplementation in Heavy Drinking Pregnant Women: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Choline, an essential nutrient, serves as a methyl-group donor for DNA methylation and is a constituent of the neurotransmitter acetylcholine and a precursor to major components of cell membranes. Findings from animal studies suggest that choline supplementation during pregnancy can mitigate adverse effects of prenatal alcohol exposure on growth and neurocognitive function. We conducted a randomized, double-blind exploratory trial to examine feasibility and acceptability of a choline supplementation intervention during pregnancy. METHODS: Seventy heavy drinkers, recruited in mid-pregnancy, were randomly assigned to receive a daily oral dose of 2 g of choline or a placebo from time of enrollment until delivery. Each dose consisted of an individually wrapped packet of powder that, when mixed with water, produced a sweet tasting grape-flavored drink. Adherence was assessed by collecting used and unused drink packets on a monthly basis and tabulating the number used. Side effects were assessed in monthly interviews. Blood samples obtained at enrollment and at 4 and 12 weeks after randomization were assayed for plasma choline concentration. RESULTS: Adherence was good-to-excellent (median doses taken = 74.0%; interquartile range = 53.9 to 88.7%) and was not related to a range of sociodemographic characteristics or to alcohol consumption ascertained using a timeline follow-back interview. By 4 weeks, plasma choline concentrations were significantly higher in the choline supplementation than the placebo arm, and this group difference continued to be evident at 12 weeks. The only side effect was a small increase in nausea/dyspepsia. No effects were seen for diarrhea, vomiting, muscle stiffness, blood pressure, or body odor changes. CONCLUSIONS: This study demonstrated that a choline supplementation program with very heavy drinkers during pregnancy is feasible even among highly disadvantaged, poorly educated women. The broad acceptability of this intervention is indicated by our finding that adherence was not related to maternal education, intellectual function, depression, nutritional status, or alcohol use.

Choline supplementation in children with fetal alcohol spectrum disorders: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Fetal alcohol spectrum disorders (FASDs) are conditions characterized by physical anomalies, neurodevelopmental abnormalities, and neurocognitive deficits, including intellectual, executive, and memory deficits. There are no specific biological treatments for FASDs, but rodent models have shown that prenatal or postnatal choline supplementation reduces cognitive and behavioral deficits. Potential mechanisms include phospholipid production for axonal growth and myelination, acetylcholine enhancement, and epigenetic effects. OBJECTIVE: Our primary goal was to determine whether postnatal choline supplementation has the potential to improve neurocognitive functioning, particularly hippocampal-dependent memory, in children with FASDs. DESIGN: The study was a double-blind, randomized, placebo-controlled pilot trial in children (aged 2.5-5 y at enrollment) with FASDs (n = 60) who received 500 mg choline or a placebo daily for 9 mo. Outcome measures were Mullen Scales of Early Learning (primary) and the elicited imitation (EI) memory paradigm (secondary). RESULTS: The administration proved feasible, and choline was well tolerated. Participants received a dose on 88% of enrolled days. The only adverse event linked to choline was a fishy body odor. Choline supplementation improved the secondary outcome (EI) only after immediate recall performance was controlled for, and the outcome was moderated by age. The treatment effect on EI items recalled was significant in the younger participants (2.5- to ≤4.0-y-olds); the young choline group showed an increase of 12-14 percentage points greater than that of the young placebo group on delayed recall measures during treatment. However, there was a marginal baseline difference in delayed item recall between the young choline and placebo groups as well as a potential ceiling effect for item recall, both of which likely contributed to the observed treatment effect. We also observed a trend toward a negative effect of choline supplementation on the immediate EI recall of ordered pairs; the young placebo group showed an increase of 8-17 percentage points greater than that of the choline group during treatment. There was an inverse relation between choline dose (in mg/kg) and memory improvement (P = 0.041); the data suggest that weight-adjusted doses may be a better alternative to a fixed dose in future studies. Limitations included trend-level baseline differences in performance, the post-hoc determination of age moderation, and potential ceiling effects for the memory measure. CONCLUSIONS: This pilot study suggests that an additional evaluation of choline supplementation as an intervention for memory functioning in children with FASDs is warranted. The observed interaction between age and choline's effect on EI suggests that potential sensitive periods should be considered in future work. This trial was registered at clinicaltrials.gov as NCT01149538.

Docosahexaenoic acid partially ameliorates deficits in social behavior and ultrasonic vocalizations caused by prenatal ethanol exposure.

Prenatal ethanol exposure disrupts social behavior in humans and rodents. One system particularly important for social behavior is the somatosensory system. Prenatal ethanol exposure alters the structure and function of this area. Docosahexaenoic acid (DHA), an omega 3 polyunsaturated fatty acid, is necessary for normal brain development and brains from ethanol-exposed animals are DHA deficient. Thus, we determined whether postnatal DHA supplementation ameliorated behavioral deficits induced by prenatal ethanol exposure. Timed pregnant Long-Evans rats were assigned to one of three groups: ad libitum access to an ethanol-containing liquid diet, pair fed an isocaloric isonutritive non-alcohol liquid diet, or ad libitum access to chow and water. Pups were assigned to one of two postnatal treatment groups; gavaged intragastrically once per day between postnatal day (P)11 and P20 with DHA (10 mg/kg in artificial rat milk) or artificial rat milk. A third group was left untreated. Isolation-induced ultrasonic vocalizations (iUSVs) were recorded on P14. Social behavior and play-induced USVs were tested on P28 or P42. Somatosensory performance was tested with a gap crossing test around P33 or on P42. Anxiety was tested on elevated plus maze around P35. Animals exposed to ethanol prenatally vocalized less, play fought less, and crossed a significantly shorter gap than control-treated animals. Administration of DHA ameliorated these ethanol-induced deficits such that the ethanol-exposed animals given DHA were no longer significantly different to control-treated animals. Thus, DHA administration may have therapeutic value to reverse some of ethanol's damaging effects.

Cholecalciferol attenuates perseverative behavior associated with developmental alcohol exposure in rats in a dose-dependent manner.

Alcohol is a known teratogen that is estimated to affect 2-5% of the births in the U.S. Prenatal alcohol exposure can produce physical features such as facial dysmorphology, physiological alterations such as cell loss in the central nervous system (CNS), and behavioral changes that include hyperactivity, cognitive deficits, and motor dysfunction. The range of effects associated with prenatal alcohol exposure is referred to as fetal alcohol spectrum disorders (FASD). Despite preventative measures, some women continue to drink while pregnant. Therefore, identifying interventions that reduce the severity of FASD is critical. This study investigated one such potential intervention, vitamin D3, a nutrient that exerts neuroprotective properties. The present study determined whether cholecalciferol, a common vitamin D3 nutritional supplement, could serve as a means of mitigating alcohol-related learning deficits. Using a rat model of FASD, cholecalciferol was given before, during, and after 3rd trimester equivalent alcohol exposure. Three weeks after cholecalciferol treatment, subjects were tested on a serial spatial discrimination reversal learning task. Animals exposed to ethanol committed significantly more errors compared to controls. Cholecalciferol treatment reduced perseverative behavior that is associated with developmental alcohol exposure in a dose-dependent manner. These data have important implications for the treatment of FASD and suggest that cholecalciferol may reduce some aspects of FASD. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

From research to practice: an integrative framework for the development of interventions for children with fetal alcohol spectrum disorders.

Since fetal alcohol syndrome was first described over 35 years ago, considerable progress has been made in the delineation of the neurocognitive profile in children with prenatal alcohol exposure. Preclinical investigators have made impressive strides in elucidating the mechanisms of alcohol teratogenesis and in testing the effectiveness of pharmacological agents and dietary supplementation in the amelioration of alcohol-induced deficits. Despite these advances, only limited progress has been made in the development of evidence-based comprehensive interventions for functional impairment in alcohol-exposed children. Having performed a search in PubMed and PsycINFO using key words, interventions, treatment, fetal alcohol syndrome, prenatal alcohol exposure, and fetal alcohol spectrum disorders, we found only 12 papers on empirically-based interventions. Only two of these interventions had been replicated and none met the criteria of "well-established," as defined by Chambless and Hollon (Journal of Consulting and Clinical Psychology 66(1):7-18, 1998). There has been only limited cross-fertilization of ideas between preclinical and clinical research with regard to the development of interventions. Therefore, we propose a framework that allows integrating data from preclinical and clinical investigations to develop comprehensive intervention programs for children with fetal alcohol spectrum disorders. This framework underscores the importance of multi-level evaluations and interventions.

Intervention for individuals with fetal alcohol spectrum disorders: treatment approaches and case management.

Exposure to alcohol in utero is considered to be the leading cause of developmental disabilities of known etiology. The most severe consequence of such exposure, fetal alcohol syndrome (FAS), is characterized by a distinct constellation of characteristic facial anomalies, growth retardation, and central nervous system (CNS) dysfunction. Some individuals with prenatal alcohol exposure (PAE) do not meet the full criteria for FAS, but instead are diagnosed with partial FAS, alcohol related neurodevelopmental disorder (ARND), or alcohol related birth defects (ARBD). The entire continuum of effects from PAE is increasingly being referred to under the umbrella term of fetal alcohol spectrum disorders (FASDs). An extensive body of research has documented major cognitive, behavioral, adaptive, social, and emotional impairments among individuals with FASDs. Although FAS was identified in the U.S. over 35 years ago, the development, evaluation, and dissemination of evidence-based interventions for individuals with FASDs have lagged behind significantly. Encouragingly, however, in recent years there has been a marked increase in efforts to design and test interventions to remediate the impairments associated with prenatal alcohol exposure. This article will review treatment needs and considerations for individuals with FASDs and their families, current empirically tested treatment approaches, case management issues, and suggestions for future directions in research on the treatment of FASDs.

Native Americans and alcohol: past, present, and future.

Native Americans have higher rates of alcohol use, frequency of use, and increased rates of fetal alcohol syndrome, compared with other ethnic groups (J. Hisnanick, 1992; P. A. May, 1996; J. M. Wallace et al., 2003). High prevalence rates of alcohol misuse among Native Americans must be understood in light of their unique history, which has resulted in trauma and exposure to many risk factors for problem alcohol use. Many risk factors have been identified in the general population; however, only some of these risk factors have been examined among Native American populations. The unique history and world view of Native Americans mean that, often, risk factors operate differently from the way they do in other populations. The authors discuss interventions and promising treatments.

Quantification of neurocognitive changes before, during, and after hyperbaric oxygen therapy in a case of fetal alcohol syndrome.

Fetal alcohol syndrome (FAS) is the most common nonhereditary cause of mental retardation, with deficits in general intellectual functioning, learning, memory, attention, and problem-solving. Presented here is the first case in which measured neurocognitive abilities were determined before, during, and after hyperbaric oxygen therapy in a case of FAS involving a teenage male patient. Memory, reaction time, and visual motor speed assessments were compared. After 40 hyperbaric treatments with 100% oxygen at 1.5 atmospheres absolute, the patient's performance in 6 of 6 categories of the computer-administered test battery improved. Word composite (verbal) scores improved from 55% to 73%, memory composite (visual) scores improved from 38% to 55%, reaction time composites improved from 1.03 to 0.53 seconds, impulse control composite scores improved from 8 to 5, and visual motor speed scores improved from 18.6 to 19.03. The patient's subjective symptoms diminished 94%. Six months after these treatments, the patient's verbal memory was maintained at 73% without any other interventions; impulsivity continued to improve, whereas other indices did not. Thirty-three additional treatments continued to improve test performance, with verbal memory at 95%, visual memory at 57%, and a 100% reduction of subjective symptoms. This patient, with 15-year-matured FAS, benefited from a short course of low-pressure hyperbaric oxygen therapy, sustained durable cognitive improvements, and continued to exhibit improvement with another short course of treatments.

Neuropsychiatric implications and long-term consequences of fetal alcohol spectrum disorders.

Prenatal alcohol exposure can cause a whole spectrum of central nervous system (CNS) sequelae that persist throughout the life span and manifest in a spectrum of effects from clinically indistinguishable to severely impairing. The greatest impact of alcohol as a teratogen is to the brain-the greatest need is for holistic treatment and management of the associated mental disorders. The interaction of this subtle brain damage with the complex psychosocial circumstances surrounding the birth of a child to a mother with alcohol problems can further compound development and result in costly and devastating social consequences. Research is urgently needed on the chronic neuropsychiatric sequelae of these subtle birth defects of the brain. Identification of these fetal alcohol spectrum disorders (FASD) in the psychiatric nomenclature is a necessary step to focus the attention and resources of the mental health field on this personally and socially significant problem.

Prevention by a silymarin/phospholipid compound of ethanol-induced social learning deficits in rats.

We explored the possibility that silymarin (SY), a fraction from Silybum marianum, might protect against the effects of in utero exposure to ethanol upon subsequent social memory function. Three groups of 8 pregnant female Sprague-Dawley rats each were provided with a liquid diet containing 35% ethanol derived calories (EDC). One experimental group received a daily subcutaneous injection of 400 mg/kg SY, the second, a 400 mg/kg oral dose of SY, a third group was maintained on the 35% EDC diet. A fourth group served as the pair-fed control group. The liquid diet regimen was maintained throughout pregnancy. Rats pups were fostered by dams in a fifth group that had been maintained on rat chow. At 90 days the pups were tested for social memory. Social recognition scores recorded for the ethanol pups were significantly poorer than those observed in both SY/ethanol groups and the chow group.

Effects of prenatal ethanol and long-chain n-3 fatty acid supplementation on development in mice. 1. Body and brain growth, sensorimotor development, and water T-maze reversal learning.

Pregnant mice were fed equivalent daily amounts of a liquid diet containing 25% (kcal) ethanol, or with maltose dextrin substituted isocalorically for ethanol. In addition, the diet contained 20% oil; this was either of two mixtures, one comprised of predominantly n-6 (18:2n-6) fatty acids, and the other containing an equivalent amount of n-6, but supplemented with a source of long chain n-3 (20:5n-3, 22:6n-3) fatty acids. An additional control group was fed lab chow ad libitum. The treatment was implemented from day 7 to 17 of gestation, whereafter all groups were fed lab chow. Ethanol decreased maternal weight gain and pup body and brain weight; it also retarded both sensory and motor development in the pups and impeded reversal learning in a water maze. The n-3 supplementation lowered maternal blood alcohol concentration, but counteracted only some of the effects of ethanol, by increasing maternal weight gain and pup body weight, and also by enhancing sensory development in the pups. Such effects were additive, in that they were also present in the maltose-dextrin control group. These findings suggest that n-3 supplementation may ameliorate some of the effects of ethanol on neurobehavioral development, but the magnitude of the effect appears to be small.

In utero alcohol heightens juvenile reactivity.

The behavioral teratogenicity of ethanol was studied in a laboratory model of the fetal alcohol syndrome. Pregnant rats were placed in one of three groups: Ethanol (4 g ethanol/kg intubated twice daily; Purina Chow ad lib.); Sucrose (7 g sucrose/kg intubated instead of ethanol; Untreated (no intubations; Purina Chow ad lib.). Ethanol offspring did not differ from either control group in neonatal body weight or developmental measures. On Day 35, 2 female offspring per litter were tested for reactivity to acoustic startle stimuli. Activity was measured during the pre-stimulus foreperiod and during inter-stimulus intervals. Ethanol pups displayed heightened startle reactivity in the absence of hyperactivity or disrupted habituation. These data indicate that ethanol in utero produces hyperreactivity in the absence of morphological, body weight or developmental abberations.