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Prenatal alcohol exposure can lead to a wide range of neurological and behavioral deficits, including alterations in motor domains. However, much less is known about the effects of prenatal cannabis exposure on motor development, despite cannabis being the most consumed illicit drug among women. Cannabis use among pregnant women has become increasingly popular given the widespread perception that consumption is safe during pregnancy. Moreover, alcohol and cannabis are commonly used together, even among pregnant women. Yet few studies have explored the potential consequences of combined prenatal exposure on behavioral domains.Using our previously established model, during gestational days 5 to 20, four groups of pregnant Sprague-Dawley rats were exposed to vaporized alcohol, delta-9-Tetrahydrocannabinol (THC) via electronic (e-) cigarettes, the combination of alcohol and THC, or a vehicle. Following birth, offspring were tested on early sensorimotor development, adolescent motor coordination, and adolescent activity levels.Prenatal THC e-cigarette exposure delayed sensorimotor development early in life and impaired motor coordination later in early adolescence; combined prenatal alcohol and THC exposure did not have additive effects on sensorimotor development. However, combined prenatal exposure produced hyperactivity among male offspring.Prenatal cannabis exposure may lead to impaired motor skills throughout early development and combined exposure with alcohol during gestation may lead to hyperactivity in early adolescence. These findings have important implications for informing pregnant women of the risks to the fetus associated with prenatal cannabis exposure, with and without alcohol, and could influence public policy.

Choline is an essential nutrient under evaluation as a cognitive enhancing treatment for fetal alcohol spectrum disorders (FASD) in clinical trials. As a result, there is increased pressure to identify therapeutic mechanism(s) of action. Choline is not only a precursor for several essential cell membrane components and signaling molecules but also has the potential to directly affect synaptic mechanisms that are believed important for cognitive processes. In the current work, we study how the direct application of choline can affect synaptic transmission in the dentate gyrus (DG) of hippocampal slices obtained from adolescent (postnatal days 21–28) Sprague–Dawley rats (Rattus norvegicus). The acute administration of choline chloride (2 mM) reliably induced a long-term depression (LTD) of field excitatory postsynaptic potentials (fEPSPs) in the DG in vitro. The depression required the involvement of M1 receptors, and the magnitude of the effect was similar in slices obtained from male and female animals. To further study the impact of choline in an animal model of FASD, we examined offspring from dams fed an ethanol-containing diet (35.5% ethanol-derived calories) throughout gestation. In slices from the adolescent animals that experienced prenatal ethanol exposure (PNEE), we found that the choline induced an LTD that uniquely involved the activation of N-methyl-d-aspartate (NMDA) and M1 receptors. This study provides a novel insight into how choline can modulate hippocampal transmission at the level of the synapse and that it can have unique effects following PNEE. NEW & NOTEWORTHY Choline supplementation is a nutraceutical therapy with significant potential for a variety of developmental disorders; however, the mechanisms involved in its therapeutic effects remain poorly understood. Our research shows that choline directly impacts synaptic communication in the brain, inducing a long-term depression of synaptic efficacy in brain slices. The depression is equivalent in male and female animals, involves M1 receptors in control animals, but uniquely involves NMDA receptors in a model of FASD.

BACKGROUND: We have recently shown that alcohol and cannabis can interact prenatally, and in a recent review paper we further identified Parvalbumin-positive (PV) interneurons in the hippocampus as a potential point of convergence for these teratogens. METHODS: A 2 (EtOH, Air) x 2 (THC, Vehicle) design was used to expose pregnant Sprague-Dawley rats to either EtOH or air, in addition to either THC or the inhalant vehicle solution, from gestational days 5–20. Immunohistochemistry was performed to detect parvalbumin-positive interneurons in one male and one female pup from each litter at post-natal day (PND) 70. RESULTS: Significant between-group, and sub-region specific, effects were found in the dorsal CA1 subfield, as well as the ventral DG. In the dorsal CA1 subfield, there was an increase in the number of PV interneurons in both the EtOH and EtOH + THC groups, but only a possible decrease with THC alone. There were fewer changes in interneuron numbers overall in the DG, however, a sex difference was found, and a decrease in the number of PV interneurons in the THC exposed group was observed in the male ventral DG. There was also an increase in cell layer volume between the EtOH + THC group and control group in the DG, and an increase from the control and THC group to the EtOH group in the CA1 region. CONCLUSIONS: Prenatal alcohol and prenatal THC exposure differentially affect parvalbumin interneuron numbers in the hippocampus, indicating that both individual and combined exposure can impact the balance of excitation and inhibition in a structure critically involved in learning and memory processes.

Among the many inclusions from the exceptionally rich fossiliferous amber of Zhangpu, China (Middle Miocene: Langhian), stingless bees (Apinae: Meliponini) are particularly common, analogous to the merely slightly older amber sites of Mexico and the Dominican Republic. While there is a large number of workers in Zhangpu amber, only two species are represented. The systematics and morphology of the tribe Meliponini is outlined, including a revision to terms of orientation and direction when discussing surfaces and features of appendages, all in order to better discuss the traits of the fossils as well as place them into a broader context in the global systematics of stingless bees. The two amber species are representative of two Old World genera of Meliponini: Tetragonula Moure and Austroplebeia Moure. While the former is widespread across southern Asia, Malesia, Papuasia, and Australia, the latter is today known only from New Guinea and Australia. Neither genus occurs in the environs of Zhangpu today. Tetragonula (Tetragonula) florilega Engel, new species, is a generally typical species of the subgenus although it intermingles traits otherwise found in two large species groups of non-Australian Tetragonula s.str. The species of Austroplebeia from Zhangpu is sufficiently distinct to place in a new subgenus, Anteplebeina Engel. Austroplebeia (Anteplebeina) fujianica Engel, new species, shares a long list of character states with Austroplebeia s.str., including the presence of yellow maculation on the face, mesoscutum, mesoscutellum, and metepisternum, found only in this clade among Asiatic Meliponini. Nonetheless, the species differs in the length of the malar space and various features of wing venation. Keys are provided to the genera in Zhangpu amber and the subgenera of both genera. The diversity of stingless bees in amber is discussed, as well as the presence of these two fossils in the Middle Miocene of mainland Asia in relation to prior divergence time estimates, phylogenetic relationships, as well as the paleogeography of the region and potential biogeographic hypotheses. The biological association of stingless bees with resins, particularly the collection of dipterocarp resins, is discussed as Zhangpu amber is a Class II resin likely produced by an extinct species of Dipterocarpaceae (Malvales). Also discussed are the ecological preferences of modern Tetragonula and Austroplebeia relative to the reconstructed paleoenvironment of the Zhangpu amber rainforest. Emendations to the classification of Meliponini are appended, with the following new taxa proposed: Atrichotrigona Engel, new subgenus of Axestotrigona Moure; Lispotrigona V.H. Gonzalez & Engel, new subgenus of Nannotrigona Cockerell; Asperplebeia Engel, new genus; Nanoplebeia Engel, new subgenus of Plebeia Schwarz; Aphaneuropsis Engel, Koilotrigona Engel, Necrotrigona Engel, Dichrotrigona Engel, Nostotrigona Engel, Ktinotrofia Engel, all new subgenera of Trigona Jurine; Chapadapis Engel, new subgenus of Schwarziana Moure. The following higher groups are also established: Hypotrigonina Engel, new sutribe; Heterotrigonitae Engel, new infratribe; Trigoniscitae Engel, new infratribe.

STUDY OBJECTIVES: Depression is prevalent among patients with sleep disorders, and studies show associations between suicidal ideation and insufficient sleep. Using retrospective clinic records, we examined positive depression screening rates among adolescent sleep clinic patients relative to other subspecialty clinic patients. We also examined relationships between sleep diagnoses and positive depression screening rate in adolescent sleep clinic patients. METHODS: Data were analyzed from patients ages 12–18 (n = 12,520) who were screened for depression using the Patient Health Questionnaire-2 (PHQ-2). Those who screened positive were administered the PHQ-9. Logistic regression was used to examine effects of age, sex, race, ethnicity, and clinic on likelihood of a positive depression screen. Within sleep clinic patients (n = 308), demographic factors, sleep disorder diagnosis, and body mass index percentile were examined using logistic and linear regression. RESULTS: Among all patients screened, older age and female sex predicted positive depression screens. Sleep clinic patients were more likely to screen positive than patients in 9 other clinics [odds ratios 2.03–6.83]. Results were similar even when the PHQ-9 sleep item was excluded [odds ratios 2.18–6.41]. Within sleep clinic patients, sleep disorder diagnosis (eg, insomnia, obstructive sleep apnea) was predictive of a positive depression screen (χ(2)(1) = 10.88, P = .004): insomnia patients were most likely to be experiencing depression. CONCLUSIONS: Adolescent sleep clinic patients are at increased risk for depressive symptoms. Among insomnia patients, risk was independent of age, sex, and obesity, suggesting a unique relationship between insomnia and affective distress, as has been found in adults. Assessing adolescents for sleep disorders should be prioritized, given the strong association with depression. CITATION: Inkelis SM, Ancoli-Israel S, Thomas JD, Bhattacharjee R. Elevated risk of depression among adolescents presenting with sleep disorders. J Clin Sleep Med. 2021;17(4):675–683.

Prenatal alcohol exposure alters brain development, affecting cognitive, motor, and emotional domains, and potentially leading to greater alcohol intake during adolescence. The present study investigated whether early alcohol exposure modifies vulnerability to behavioral alterations associated with adolescent alcohol exposure in a rodent model.Sprague-Dawley rats received ethanol or sham intubations during two developmental periods: (1) the third trimester equivalent of brain development in humans (postnatal days [PD] 4-9) and (2) adolescence (PD 28-42). Both exposures resulted in blood alcohol concentrations around 200 mg/dl. Subjects were tested in the open field (PD 45-48) and on hippocampal and prefrontal cortical (PFC) dependent tasks: the Morris water maze (PD 52-58) and trace fear conditioning (PD 63-64).Neonatal alcohol exposure reduced forebrain and cerebellar weight, increased open-field activity, and slowed acquisition of trace fear conditioning. Adolescent alcohol exposure did not disrupt learning or significantly induce gross brain pathology, suggesting that 200 mg/dl/day of ethanol disrupts cognitive development during the 3rd trimester equivalent, but not during adolescence. Interestingly, females exposed to alcohol only during adolescence exhibited an increased conditioned fear response and more rapid habituation of locomotor activity in the open field, suggesting alterations in emotional responding. Moreover, subjects exposed to a combination of neonatal and adolescent alcohol exposure spent significantly more time in the center of the open field chamber than other groups. Similarly, males exposed to the combination exhibited less thigmotaxis in the Morris water maze.These results indicate that combined exposure to alcohol during these two critical periods reduces anxiety-related behaviors and/or increases risk taking in a sex-dependent manner, suggesting that prenatal alcohol exposure may affect risk for emotional consequences of adolescent alcohol exposure.

Prenatal alcohol exposure can disrupt the development of numerous systems, including the immune system. Indeed, alterations in cytokine levels may contribute to the neuropathological, behavioral, and cognitive problems, and other adverse outcomes observed in individuals with fetal alcohol spectrum disorders. Importantly, supplementation with the essential nutrient choline can improve performance in hippocampal-dependent behaviors; thus, the present study examined the effects of choline on plasma and hippocampal cytokines in adult rats exposed to ethanol in early development. From postnatal day (PD) 4–9 (third trimester equivalent), pups received ethanol (5.25 g/kg/day) or Sham intubations. Subjects were treated with choline chloride (100 mg/kg/day) or saline from PD10–30. On PD60, plasma and hippocampal tissue was collected before and after an immune challenge (lipopolysaccharide (LPS); 50 ug/kg). Prior to the immune challenge, ethanol-exposed subjects showed an overall increase in hippocampal pro-inflammatory cytokines, an effect mitigated by choline supplementation. In contrast, in the plasma, choline reduced LPS-related increases in pro-inflammatory markers, particularly in ethanol-exposed subjects. Thus, early choline supplementation may modify both brain and peripheral inflammation. These results suggest that early choline can mitigate some long-term effects of ethanol exposure on hippocampal inflammation, which may contribute to improved hippocampal function, and could also influence peripheral immune responses that may impact overall health.

Prenatal ethanol exposure (PNEE) is a leading cause of neurodevelopmental impairments, yet treatments for individuals with PNEE are limited. Importantly, postnatal supplementation with the essential nutrient choline can attenuate some adverse effects of PNEE on cognitive development; however, the mechanisms of action for choline supplementation remain unclear. This study used an animal model to determine if choline supplementation could restore hippocampal synaptic plasticity that is normally impaired by prenatal alcohol. Throughout gestation, pregnant Sprague Dawley rats were fed an ethanol liquid diet (35.5% ethanol-derived calories). Offspring were injected with choline chloride (100 mg/kg/day) from postnatal days (PD) 10–30, and then used for in vitro electrophysiology experiments as juveniles (PD 31–35). High-frequency conditioning stimuli were used to induce long-term potentiation (LTP) in the medial perforant path input to the dentate gyrus of the hippocampus. PNEE altered synaptic transmission in female offspring by increasing excitability, an effect that was mitigated with choline supplementation. In contrast, PNEE juvenile males had decreased LTP compared to controls, and this was rescued by choline supplementation. These data demonstrate sex-specific changes in plasticity following PNEE, and provide evidence that choline-related improvements in cognitive functioning may be due to its positive impact on hippocampal synaptic physiology.

Prenatal alcohol exposure (PAE) is associated with smaller regional and global brain volumes. In rats, gestational choline supplementation mitigates adverse developmental effects of ethanol exposure. Our recent randomized, double-blind, placebo-controlled maternal choline supplementation trial showed improved somatic and functional outcomes in infants at 6.5 and 12 months postpartum. Here, we examined whether maternal choline supplementation protected the newborn brain from PAE-related volume reductions and, if so, whether these volume changes were associated with improved infant recognition memory.Fifty-two infants born to heavy-drinking women who had participated in a choline supplementation trial during pregnancy underwent structural magnetic resonance imaging with a multi-echo FLASH protocol on a 3T Siemens Allegra MRI (median age = 2.8 weeks postpartum). Subcortical regions were manually segmented. Recognition memory was assessed at 12 months on the Fagan Test of Infant Intelligence (FTII). We examined the effects of choline on regional brain volumes, whether choline-related volume increases were associated with higher FTII scores, and the degree to which the regional volume increases mediated the effects of choline on the FTII.Usable MRI data were acquired in 50 infants (choline: n = 27; placebo: n = 23). Normalized volumes were larger in six of 12 regions in the choline than placebo arm (t ≥ 2.05, p ≤ 0.05) and were correlated with the degree of maternal choline adherence (β ≥ 0.28, p ≤ 0.04). Larger right putamen and corpus callosum were related to higher FTII scores (r = 0.36, p = 0.02) with a trend toward partial mediation of the choline effect on recognition memory.High-dose choline supplementation during pregnancy mitigated PAE-related regional volume reductions, with larger volumes associated with improved 12-month recognition memory. These results provide the first evidence that choline may be neuroprotective against PAE-related brain structural deficits in humans.

In the United States, nicotine and cannabis are the most common licit and illicit drugs used among pregnant women. Importantly, nicotine and cannabis are now being combined for consumption via e-cigarettes, an increasingly popular route of administration. Both nicotine and tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, cross the placenta barrier. However, the consequences of prenatal cannabis use are not well understood, and less is known about potential combination effects when consumed with nicotine, especially via e-cigarettes. The present study used a rodent model to examine how prenatal e-cigarette exposure to nicotine, THC, and the combination impacts motor development among offspring. Pregnant Sprague-Dawley rats were exposed to nicotine (36 mg/mL), THC (100 mg/mL), the combination, or vehicle via e-cigarette inhalation from gestational days (GD) 5-20. One sex pair per litter was tested on an early sensorimotor development task (postnatal days [PD] 12-20) and a parallel bar motor coordination task (PD 30-32). Combined prenatal exposure to nicotine and THC delayed sensorimotor development, even though neither drug produced impairments on their own. In contrast, prenatal exposure to either nicotine or THC impaired motor coordination, whereas combined exposure exacerbated these effects, particularly among females. These data illustrate that prenatal exposure to either nicotine or THC may alter motor development, and that the combination may produce more severe effects. These findings have important implications for pregnant women as we better understand the teratogenic effects of these drugs consumed via e-cigarettes.

Cannabis is the most commonly used illicit drug among pregnant women, and rates are likely to increase given recent legalization. In addition, half of pregnant women who report consuming cannabis also report drinking alcohol. However, little is known about the consequences of prenatal cannabis alone or combination with alcohol, particularly with cannabis products that are continually increasing in potency of the primary psychoactive constituent in cannabis, Δ9-tetrahydrocannabinol (THC). The current study investigated the effects of early exposure to cannabinoids during the brain growth spurt on early physical and motor development alone (Experiment 1) or in combination with alcohol (Experiment 2). In Experiment 1, Sprague-Dawley rat pups were exposed to a cannabinoid receptor agonist (CP-55,940 [CP]; 0.1, 0.25, 0.4 mg/kg/day), the drug vehicle, or a saline control from postnatal days (PD) 4-9. In Experiment 2, rat pups were exposed to CP (0.4 mg/kg/day) or the vehicle, and were additionally intubated with alcohol (11.9% v/v; 5.25 g/kg/day) or received a sham intubation. Subjects in both experiments were tested on a motor development task (PD 12-20) and a motor coordination task during adolescence (PD 30-32). Both developmental cannabinoid and alcohol exposure separately decreased body growth throughout development, and combined exposure exacerbated these effects, although only alcohol exposure induced long-term body weight reductions. Developmental cannabinoid exposure advanced early motor development, whereas alcohol exposure delayed development, and subjects given combined exposure did not differ from controls on some measures. Alcohol exposure impaired motor coordination later in life. In contrast, cannabinoid exposure, by itself did not significantly affect long-term motor coordination, but did exacerbate alcohol-related impairments in motor coordination among females. These results suggest that cannabinoid exposure may not only alter development by itself, but may exacerbate alcohol’s teratogenic effects in specific behavioral domains. These findings have important implications not only for individuals affected by prenatal exposure, but also for establishing public policy for women regarding cannabis use during pregnancy.

Nicotine and cannabis are two of the most commonly consumed licit and illicit drugs during pregnancy, often consumed together via e-cigarettes. Vaping is assumed to be a safer alternative than traditional routes of consumption, yet the potential consequences of prenatal e-cigarette exposure are largely unknown, particularly when these two drugs are co-consumed. In a novel co-exposure model, pregnant Sprague-Dawley rats received nicotine (36 mg/mL), THC (100 mg/mL), the combination, or the vehicle via e-cigarettes daily from gestational days 5-20, mimicking the first and second human trimesters. Maternal blood samples were collected throughout pregnancy to measure drug and metabolite levels, and core body temperatures before and after exposure were also measured. Pregnant dams exposed to combined nicotine and THC had lower plasma nicotine and cotinine levels than those exposed to nicotine alone; similarly, the combined exposure group also had lower plasma THC and THC metabolite (THC-OH and THC-COOH) levels than those exposed to THC alone. Prenatal nicotine exposure gradually decreased basal core body temperatures each day, with chronic exposure, whereas exposure to THC alone decreased temperatures during the individual sessions. Despite these physiological effects, no changes were observed in food or water intake, weight gain, or basic litter outcomes. These data suggest that combined exposure to nicotine and THC elicits both separate and interactive physiological effects of nicotine and THC on pregnant dams. These data and use of this model can help improve education for pregnant mothers about prenatal e-cigarette use and has important implications for public policy.HIGHLIGHTSRepeated prenatal nicotine exposure via e-cigarettes gradually decreased temperaturesPrenatal THC exposure via e-cigarettes decreased temperatures during intoxicationCombined prenatal exposure via e-cigarettes altered plasma drug and metabolite levelsThis co-exposure model elicits separate and interactive effects of nicotine and THC

It has been well established that prenatal alcohol exposure can lead to a wide range of neurological and behavioral deficits, including alterations in motor domains. However, much less is known about the effects of prenatal cannabis exposure on motor development, despite the fact that cannabis is the most commonly consumed illicit drug among women. Cannabis use among pregnant women has become increasingly popular given the wide-spread perception that consumption is safe during pregnancy. Moreover, alcohol and cannabis are commonly used together, even among pregnant women. Yet, few studies have explored the potential consequences of combined prenatal exposure on behavioral domains. Using our previously established model, pregnant Sprague-Dawley rats were exposed to vaporized alcohol, THC via e-cigarettes, the combination, or a vehicle from gestational days 5-20. Following birth, offspring were tested on early sensorimotor development, adolescent motor coordination, and adolescent activity levels. Prenatal e-cigarette THC exposure delayed sensorimotor development early in life and impaired motor coordination later in adolescence. However, combined prenatal alcohol and THC exposure produced hyperactivity among male offspring. These data suggest that prenatal cannabis exposure may lead to impaired motor skills throughout early development, and that combined exposure with alcohol during gestation may also lead to hyperactivity in adolescence. These findings have important implications for pregnant women and public policy.

Cannabis is the most frequently used illicit drug among pregnant women, yet the potential consequences of prenatal cannabis exposure on development are not well understood. Electronic cigarettes have become an increasingly popular route of administration among pregnant women, in part to user’s perception that e-cigarettes are a safer route for consuming cannabis products. Importantly, half of pregnant women who consume cannabis also report consuming alcohol, but research investigating co-consumption of these drugs is limited, particularly with current routes of administration. The purpose of this study was to establish a co-exposure vapor inhalation model of alcohol and THC in pregnant rats, to ultimately determine the effects on fetal development. Pregnant Sprague-Dawley rats were exposed to moderate doses of THC via e-cigarettes, alcohol, the combination, or vehicle daily from gestational days 5-20. Importantly, pharmacokinetic interactions of alcohol and THC were observed during pregnancy. Combined exposure consistently increased blood alcohol concentrations, indicating that THC alters alcohol metabolism. In addition, THC levels also increased over the course of pregnancy and THC metabolism was altered by alcohol. Physically, alcohol, but not THC, exposure during pregnancy reduced maternal weight gain, an effect not due to differences in food intake, which did not vary group. Neither prenatal alcohol nor THC exposure altered gestational length, litter size, sex ratio or birth weight. However, prenatal alcohol exposure delayed eye opening, and prenatal THC exposure decreased body weights during adolescence among offspring. These individual and synergistic effects suggest that this novel co-exposure vapor inhalation paradigm effectively induces intoxication in pregnant dams and exerts some effects on fetal development, while avoiding nutritional confounds, birth complications, or changes in litter size. With this model, we have demonstrated that combining THC and alcohol alters drug metabolism, which could have important consequences on prenatal development. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Cannabis is the most commonly used illicit drug among pregnant women. Moreover, over half of pregnant women who are consuming cannabis are also consuming alcohol; however, the consequences of combined prenatal alcohol and cannabis exposure on fetal development are not well understood. The current study examined behavioral development following exposure to ethanol (EtOH) and/or CP-55,940 (CP), a cannabinoid receptor agonist. From postnatal days (PD) 4–9, a period of brain development equivalent to the third trimester, Sprague–Dawley rats received EtOH (5.25 g/kg/day) or sham intubation, as well as CP (0.4 mg/kg/day) or vehicle. All subjects were tested on open field activity (PD 18–21), elevated plus maze (PD 25), and spatial learning (PD 40–46) tasks. Both EtOH and CP increased locomotor activity in the open field, and the combination produced more severe overactivity than either exposure alone. Similarly, increases in thigmotaxis in the Morris water maze were caused by either EtOH or CP alone, and were more severe with combined exposure, although only EtOH impaired spatial learning. Finally, developmental CP significantly increased time spent in the open arms on the elevated plus maze. Overall, these data indicate that EtOH and CP produce some independent effects on behavior, and that the combination produces more severe overactivity in the open field. Importantly, these data suggest that prenatal cannabis disrupts development and combined prenatal exposure to alcohol and cannabis may be particularly damaging to the developing fetus, which has implications for the lives of affected individuals and families and also for establishing public health policy.

Background Impaired motor function in children with histories of prenatal exposure to alcohol has been previously reported but, to date, no studies using quantitatively based analyses have been performed to assess gait in these children. Methods Gait of children with (n = 18) or without (n = 26) prenatal alcohol exposure was assessed using an electronically instrumented walkway. Children completed blocks of trials traversing the walkway with different combinations of walking condition (increased, self-paced, and decreased cadence) and direction (forward and backward). Gait velocity, cadence, stride length, step width, foot angle, and double support time, as well as the variability of these temporal–spatial markers, were used to assess gait. Results Results indicated that, in comparison with typically developing children, alcohol-exposed children produced exaggerated foot angle and increased step width. Additionally, alcohol-exposed children produced greater intrasubject variability of gait velocity and walking cadence while walking forward and backward, and greater variability in step width when walking backward and for all 3 walking conditions. Conclusions The results indicate that selected gait markers are adversely affected by prenatal exposure to alcohol. Clinicians and front-line personnel (e.g., teachers) should provide movement enriched experiences to help ameliorate these alcohol-related deficits.

The current profile of gait control in children with ADHD is incomplete and predominately based on children walking forward at a self-selected pace. There are no studies of potential gait deficits in this clinical population when walking in different directions in combination with varying rates of stepping that are freely selected and entrained to an external stimulus. The purpose of the current study was to address this lack of information by assessing gait of children aged 7–17 years with (n = 17) and without (n = 26) ADHD. Participants walked forward and backward along an electronically instrumented carpet at a self-selected stepping rate and in synchrony to a metronome that dictated an increased and decreased stepping rate. Using repeated measures analysis of covariance (ANCOVA) to assess spatiotemporal gait parameters, results showed that children with ADHD exhibited a significantly exaggerated, toes ‘turned out,’ foot position for all walking conditions compared to typically developing children. When walking backward, children with ADHD produced an increased step width, higher stepping cadence, and increased velocity. Additionally, coefficient of variation ratios indicated that children with ADHD produced greater variability of velocity, cadence, and step time for all walking conditions, and greater variability for stride length when walking at an increased stepping rate. Results were interpreted in terms of clinical significance and practical ramifications that inform rehabilitation specialists in designing therapies that ameliorate the reported gait deficits.

Background Marijuana and alcohol are both substances that, when used during pregnancy, may have profound effects on the developing fetus. There is evidence to suggest that both drugs have the capacity to affect working memory, one function of the hippocampal formation; however, there is a paucity of data on how perinatal exposure to alcohol or cannabis impacts the process of adult neurogenesis. Methods This systematic review examines immunohistochemical data from adult rat and mouse models that assess perinatal alcohol or perinatal marijuana exposure. A comprehensive list of search terms was designed and used to search 3 separate databases. All results were imported to Mendeley and screened by 2 authors. Consensus was reached on a set of final papers that met the inclusion criteria, and their results were summarized. Results Twelve papers were identified as relevant, 10 of which pertained to the effects of perinatal alcohol on the adult hippocampus, and 2 pertained to the effects of perinatal marijuana on the adult hippocampus. Cellular proliferation in the dentate gyrus was not affected in adult rats and mice exposed to alcohol perinatally. In general, perinatal alcohol exposure did not have a significant and reliable effect on the maturation and survival of adult born granule neurons in the dentate gyrus. In contrast, interneuron numbers appear to be reduced in the dentate gyrus of adult rats and mice exposed perinatally to alcohol. Perinatal marijuana exposure was also found to reduce inhibitory interneuron numbers in the dentate gyrus. Conclusions Perinatal alcohol exposure and perinatal marijuana exposure both act on inhibitory interneurons in the hippocampal formation of adult rats. These findings suggest simultaneous perinatal alcohol and marijuana exposure (SAM) may have a dramatic impact on inhibitory processes in the dentate gyrus.

Children’s Hospitals’ Solutions for Patient Safety (SPS) is a network of over 140 children’s hospitals who share the vision of working together to eliminate serious harm across all pediatric hospitals. The SPS network is built on the fundamental belief that by sharing successes and failures transparently and learning from one another, children’s hospitals can achieve their goals more effectively and quickly than working alone. Each year, SPS hosts National Learning Sessions to which members are invited to submit abstracts describing relevant safety research or improvement work. The following abstracts were among the top submitted for the SPS Spring 2021 National Learning Session.

Prenatal alcohol exposure can cause a range of physical and behavioral alterations; however, the outcome among children exposed to alcohol during pregnancy varies widely. Some of this variation may be due to nutritional factors. Indeed, higher rates of fetal alcohol spectrum disorders (FASD) are observed in countries where malnutrition is prevalent. Epidemiological studies have shown that many pregnant women throughout the world may not be consuming adequate levels of choline, an essential nutrient critical for brain development, and a methyl donor. In this study, we examined the influence of dietary choline deficiency on the severity of fetal alcohol effects. Pregnant Sprague-Dawley rats were randomly assigned to receive diets containing 40, 70, or 100% recommended choline levels. A group from each diet condition was exposed to ethanol (6.0 g/kg/day) from gestational day 5 to 20 via intubation. Pair-fed and ad lib lab chow control groups were also included. Physical and behavioral development was measured in the offspring. Prenatal alcohol exposure delayed motor development, and 40% choline altered performance on the cliff avoidance task, independent of one another. However, the combination of low choline and prenatal alcohol produced the most severe impairments in development. Subjects exposed to ethanol and fed the 40% choline diet exhibited delayed eye openings, significantly fewer successes in hind limb coordination, and were significantly overactive compared to all other groups. These data suggest that suboptimal intake of a single nutrient can exacerbate some of ethanol’s teratogenic effects, a finding with important implications for the prevention of FASD.

Background Prenatal alcohol exposure results in a broad range of cognitive and behavioral impairments. Because of the long-lasting problems that are associated with fetal alcohol spectrum disorders (FASDs), the development of effective treatment programs is critical. Preclinical animal studies have shown that choline, which is an essential nutrient, can attenuate the severity of alcohol-related cognitive impairments. Objective We aimed to translate preclinical findings to a clinical population to investigate whether choline supplementation can ameliorate the severity of memory, executive function, and attention deficits in children with FASDs. Design In the current study, which was a randomized, double-blind, placebo-controlled clinical trial, we explored the effectiveness of a choline intervention for children with FASDs who were aged 5-10 y. Fifty-five children with confirmed histories of heavy prenatal alcohol exposure were randomly assigned to either the choline (n = 29) or placebo (n = 26) treatment arms. Participants in the choline group received 625 mg choline/d for 6 wk, whereas subjects in the placebo group received an equivalent dose of an inactive placebo treatment. Primary outcomes, including the performance on neuropsychological measures of memory, executive function, and attention and hyperactivity, were assessed at baseline and postintervention. Results Compared with the placebo group, participants in the choline group did not differentially improve in cognitive performance in any domain. Treatment compliance and mean dietary choline intake were not predictive of treatment outcomes. Conclusions Findings of the current study do not support that choline, administered at a dose of 625 mg/d for 6 wk, is an effective intervention for school-aged (5-10 y old) children with FASDs. This research provides important information about choline's therapeutic window. Combined with other studies of choline and nutritional interventions in this population, this study emphasizes a further need for the continued study of the role of nutritional status and supplementation in children with FASDs and the contributions of nutrition to neurocognition. This trial was registered at clinicaltrials.gov as NCT01911299.

Background Nutrition is an important factor that affects brain development. Nutritional deficiencies can exacerbate alcohol's damaging effects. Conversely, nutritional supplementation can serve a protective role against alcohol damage and may prove to be a worthwhile intervention strategy. This study investigated dietary intake in school-aged children with heavy prenatal alcohol exposure to understand their nutritional status, compared to a national sample of typically developing children and Dietary Reference Intakes. Methods Dietary intake data were collected from children with confirmed histories of heavy prenatal alcohol exposure (5 to 10 years, n = 55) using the Automated Self-Administered 24-Hour Dietary Recall (ASA24). Observed nutrient levels were compared to the Dietary Reference Intakes to evaluate adequacy of nutrient intake as well as to national averages for same-aged children (What We Eat in America, NHANES 2007–2008). Results Alcohol-exposed children exhibited poorer nutritional status compared to the typically developing NHANES sample, consuming lower levels of protein, omega-3 fatty acids, magnesium, potassium, zinc, vitamins C and K, niacin, and choline. Moreover, their diets did not meet Recommended Dietary Allowance or Adequate Intake for dietary fiber, potassium, vitamins E and K, omega-3 fatty acids, and choline. Conclusions The present findings are consistent with prior studies investigating nutritional intake in preschoolers with FASD, indicating that these children are vulnerable to nutritional inadequacies. Moreover, data suggest a specific profile of dietary intake in this population. As several nutrients are important for cognitive development, targeted interventions in clinical populations might be effective in boosting outcomes. Thus, further clinical investigation into the role of nutrition in improving cognitive outcomes is warranted.

Prenatal exposure to alcohol can result in a range of neurobehavioral impairments and physical abnormalities. The term fetal alcohol spectrum disorders (FASD) encompasses the outcomes of prenatal alcohol exposure (PAE), the most severe of which is fetal alcohol syndrome (FAS). These effects have lifelong consequences, placing a significant burden on affected individuals, caregivers, and communities. Caregivers of affected children often report that their child has sleep problems, and many symptoms of sleep deprivation overlap with the cognitive and behavioral deficits characteristic of FASD. Alcohol-exposed infants and children demonstrate poor sleep quality based on measures of electroencephalography (EEG), actigraphy, and questionnaires. These sleep studies indicate a common theme of disrupted sleep pattern, more frequent awakenings, and reduced total sleep time. However, relatively little is known about circadian rhythm disruption, and the neurobehavioral correlates of sleep disturbance in individuals with PAE. Furthermore, there is limited information available to healthcare providers about identification and treatment of sleep disorders in patients with FASD. This review consolidates the findings from studies of infant and pediatric sleep in this population, providing an overview of typical sleep characteristics, neurobehavioral correlates of sleep disruption, and potential avenues for intervention in the context of PAE.

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 D 3 , a nutrient that exerts neuroprotective properties. The present study determined whether cholecalciferol, a common vitamin D 3 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’.

To extend our current understanding of the teratogenic effects of prenatal alcohol exposure on the control of isometric force, the present study investigated the signal characteristics of power spectral density functions resulting from sustained control of isometric force by children with and without heavy prenatal exposure to alcohol. It was predicted that the functions associated with the force signals would be fundamentally different for the two groups. Twenty-five children aged between 7 and 17 years with heavy prenatal alcohol exposure and 21 non-alcohol exposed control children attempted to duplicate a visually represented target force by pressing on a load cell. The level of target force (5 and 20% of maximum voluntary contraction) and the time interval between visual feedback (20ms, 320ms and 740ms) were manipulated. A multivariate spectral estimation method with sinusoidal windows was applied to individual isometric force-time signals. Analysis of the resulting power spectral density functions revealed that the alcohol-exposed children had a lower mean frequency, less spectral variability, greater peak power and a lower frequency at which peak power occurred. Furthermore, mean frequency and spectral variability produced by the alcohol-exposed group remained constant across target load and visual feedback interval, suggesting that these children were limited to making long-time scale corrections to the force signal. In contrast, the control group produced decreased mean frequency and spectral variability as target force and the interval between visual feedback increased, indicating that when feedback was frequently presented these children used the information to make short-time scale adjustments to the ongoing force signal. Knowledge of these differences could facilitate the design of motor rehabilitation exercises that specifically target isometric force control deficits in alcohol-exposed children.

Prenatal alcohol exposure can result in a range of physical, neuropathological, and behavioral alterations, collectively termed fetal alcohol spectrum disorders (FASD). We have shown that supplementation with the nutrient choline reduces the severity of developmental alcohol-associated deficits in hippocampal-dependent behaviors and normalizes some aspects of hippocampal cholinergic development and DNA methylation patterns. Alcohol's developmental effects may also be mediated, in part, by altering microRNAs (miRNAs) that serve as negative regulators of gene translation. To determine whether choline supplementation alters ethanol's long-lasting effects on miRNAs, Sprague-Dawley rats were exposed to 5.25 g/kg/day ethanol from postnatal days (PD) 4-9 via intubation; controls received sham intubations. Subjects were treated with choline chloride (100 mg/kg/day) or saline vehicle subcutaneously (s.c.) from PD 4-21. On PD 22, subjects were sacrificed, and RNA was isolated from the hippocampus. MiRNA expression was assessed with TaqMan Human MicroRNA Panel Low-Density Arrays. Ethanol significantly increased miRNA expression variance, an effect that was attenuated with choline supplementation. Cluster analysis of stably expressed miRNAs that exceeded an ANOVA p 0.05 criterion indicated that for both male and female offspring, control and ethanol-exposed groups were most dissimilar from each other, with choline-supplemented groups in between. MiRNAs that expressed an average 2-fold change due to ethanol exposure were further analyzed to identify which ethanol-sensitive miRNAs were protected by choline supplementation. We found that at a false discovery rate (FDR)-adjusted criterion of p 0.05, miR-200c was induced by ethanol exposure and that choline prevented this effect. Collectively, our data show that choline supplementation can normalize disturbances in miRNA expression following developmental alcohol exposure and can protect specific miRNAs from induction by ethanol. These findings have important implications for the mechanisms by which choline may serve as a potential treatment for FASD.

Background Heavy prenatal alcohol exposure can result in diverse and extensive damage to the central nervous system, including the cerebellum, basal ganglia, and cerebral cortex. Given that these brain regions are involved in the generation and maintenance of motor force, we predicted that prenatal alcohol exposure would adversely affect this parameter of motor control. We previously reported that children with gestational alcohol exposure experience significant deficits in regulating isometric (i.e., constant) force. The purpose of this study was to determine whether these children exhibit similar deficits when producing isotonic (i.e., graded) force. Methods Children with heavy prenatal alcohol exposure and typically developing children completed a series of isotonic force contractions by exerting force on a load cell to match a criterion target force displayed on a computer monitor. Two levels of target force (5 or 20% of maximum voluntary force) were investigated in combination with varying levels of visual feedback. Results Compared with control children, children with heavy prenatal alcohol exposure generated isotonic force signals that were less accurate, more variable, and less complex in the time domain. Specifically, interactions were found between group and visual feedback for response accuracy and signal complexity, suggesting that these children have greater difficulty altering their motor output when visual feedback is low. Conclusions These data suggest that prenatal alcohol exposure produces deficits in regulating isotonic force, which presumably result from alcohol-related damage to developing brain regions involved in motor control. These children will most likely experience difficulty performing basic motor skills and daily functional skills that require coordination of finely graded force. Therapeutic strategies designed to increase feedback and, consequently, facilitate visual-motor integration could improve isotonic force production in these children.

Some of the most frequent deficits seen in children with fetal alcohol spectrum disorders (FASD) and in animal models of FASD are spatial memory impairments and impaired executive functioning, which are likely related to alcohol-induced alterations of the hippocampus and prefrontal cortex (PFC), respectively. Choline, a nutrient supplement, has been shown in a rat model to ameliorate some of alcohol's teratogenic effects, and this effect may be mediated through choline's effects on DNA methylation.Alcohol was given by intragastric intubation to rat pups during the neonatal period (postnatal days 2 to 10) (ET group), which is equivalent to the third trimester in humans and a period of heightened vulnerability of the brain to alcohol exposure. Control groups included an intubated control group given the intubation procedure without alcohol (IC) and a nontreated control group (NC). Choline or saline was administered subcutaneously to each subject from postnatal days 2 to 20. On postnatal day 21, the brains of the subjects were removed and assayed for global DNA methylation patterning as measured by chemiluminescence using the cpGlobal assay in both the hippocampal region and PFC.Alcohol exposure caused hypermethylation in the hippocampus and PFC, which was significantly reduced after choline supplementation. In contrast, control animals showed increases in DNA methylation in both regions after choline supplementation, suggesting that choline supplementation has different effects depending upon the initial state of the brain.This study is the first to show changes in global DNA methylation of the hippocampal region and PFC after neonatal alcohol exposure. Choline supplementation impacts global DNA methylation in these 2 brain regions in alcohol-exposed and control animals in a differential manner. The current findings suggest that both alcohol and choline have substantial impact on the epigenome in the PFC and hippocampus, and future studies will be needed to describe which gene families are impacted in such a way that function of the nervous system is changed.

Prenatal alcohol exposure leads to long-lasting cognitive and attention deficits, as well as hyperactivity. Using a rat model, we have previously shown that perinatal supplementation with the essential nutrient, choline, can reduce the severity of some fetal alcohol effects, including hyperactivity and deficits in learning and memory. In fact, choline can mitigate alcohol-related learning deficits even when administered after developmental alcohol exposure, during the postnatal period. However, it is not yet known how choline is able to mitigate alcohol-related behavioral alterations. Choline may act by altering cholinergic signaling in the hippocampus. This study examined the effects of developmental alcohol exposure and perinatal choline supplementation on hippocampal M(1) and M(2/4) muscarinic receptors. Sprague-Dawley rat pups were orally intubated with ethanol (5.25 mg/kg/day) from postnatal days (PD) 4-9, a period of brain development equivalent to the human third trimester; control subjects received sham intubations. From PD 4-30, subjects were injected s.c. with choline chloride (100 mg/kg/day) or saline vehicle. Open field activity was assessed from PD 30 through 33, and brain tissue was collected on PD 35 for autoradiographic analysis. Ethanol-exposed subjects were more active compared to controls during the first 2 days of testing, an effect attenuated with choline supplementation. Developmental alcohol exposure significantly decreased the density of muscarinic M(1) receptors in the dorsal hippocampus, an effect that was not altered by choline supplementation. In contrast, developmental alcohol exposure significantly increased M(2/4) receptor density, an effect mitigated by choline supplementation. In fact, M(2/4) receptor density of subjects exposed to alcohol and treated with choline did not differ significantly from that of controls. These data suggest that developmental alcohol exposure can cause long-lasting changes in the hippocampal cholinergic system and that perinatal choline supplementation may attenuate alcohol-related behavioral changes by influencing cholinergic systems.

Background Production of isometric (i.e., constant) force is an essential component of performing every day functional tasks, yet no studies have investigated how this type of force is regulated in children with confirmed histories of heavy prenatal alcohol exposure.

Background The third trimester in human fetal development represents a critical time of brain maturation referred to as the “brain growth spurt”. This period occurs in rats postnatally, and exposure to ethanol during this time can increase the risk of impairments on a variety of cognitive and motor tasks. It has been proposed that one potential mechanism for the teratogenic effects of ethanol is NMDA receptor-mediated excitotoxicity during periods of ethanol withdrawal. In neonatal rats, antagonism of NMDA receptors during ethanol withdrawal, with drugs such as MK-801 and eliprodil, has been shown to mitigate some of the behavioral deficits induced by developmental ethanol exposure. The current study examined whether memantine, an NMDA receptor antagonist and a drug used clinically in Alzheimer's patients, would attenuate impairments associated with binge ethanol exposure in neonatal rats. Methods On postnatal day 6, rats were exposed to 6 g/kg ethanol via intubation with controls receiving an isocaloric maltose dextrin solution. Twenty-one hours following the ethanol binge, rats received intraperitoneal injections of memantine at 0, 10, 15, or 20 mg/kg. Ethanol's teratogenic effects were assessed using multiple behavioral tasks: open field activity, parallel bars and spatial discrimination reversal learning. Results Ethanol-treated rats were overactive in the open field and were impaired on both reversal learning and motor performance. Administration of 15 or 20 mg/kg memantine during withdrawal significantly attenuated ethanol's adverse effects on motor coordination, but did not significantly alter activity levels or improve the spatial learning deficits associated with neonatal alcohol exposure. Conclusion These results indicate that a single memantine administration during ethanol withdrawal can mitigate motor impairments but not spatial learning impairments or overactivity observed following a binge ethanol exposure during development in the rat.

Children exposed to alcohol prenatally suffer from a range of physical, neuropathological and behavioral alterations, referred to as Fetal Alcohol Spectrum Disorders (FASD). Both the cerebellum and hippocampus are affected by alcohol exposure during development, which may contribute to behavioral and cognitive deficits observed in children with FASD. Despite the known neuropathology associated with prenatal alcohol exposure, many pregnant women continue to drink (heavy drinkers, in particular), creating a need to identify effective treatments for their children who are adversely affected by alcohol. We previously reported that choline supplementation can mitigate alcohol’s effects on cognitive development, specifically on tasks which depend on the functional integrity of the hippocampus. The present study examined whether choline supplementation could differentially mitigate ethanol’s effects on trace eyeblink classical conditioning (a hippocampal-dependent task) and delay eyeblink classical conditioning (a cerebellar-dependent task). Long-Evans rats were exposed to 5.25 g/kg/day alcohol via gastric intubation from postnatal days (PD) 4-9, a period of brain development equivalent to late gestation in humans. A sham-intubated control group was included. From PD 10-30, subjects received subcutaneous injections of 100 mg/kg choline chloride or vehicle. Beginning on PD 32-34, subjects were trained on either delay or trace eyeblink conditioning. Performance of subjects exposed to alcohol was significantly impaired on both tasks, as indicated by significant reductions in percentage and amplitude of conditioned eyeblink responses, an effect that was attenuated by choline supplementation on the trace, but not delay conditioning task. Indeed, ethanol-exposed subjects treated with choline performed at control levels on the trace eyeblink conditioning task. There were no significant main or interactive effects of sex. These data indicate that choline supplementation can significantly reduce the severity of trace eyeblink conditioning deficits associated with early alcohol exposure, even when administered after the alcohol insult is complete. These findings have important implications for the treatment of fetal alcohol spectrum disorders.

Background: Alcohol consumption during pregnancy can damage the developing fetus, illustrated by central nervous system dysfunction and deficits in motor and cognitive abilities. Binge drinking has been associated with an increased risk of fetal alcohol spectrum disorders, likely due to increased episodes of ethanol withdrawal. We hypothesized that overactivity of the N-methylD-aspartate (NMDA) receptor during ethanol withdrawal leads to excitotoxic cell death in the developing brain. Consistent with this, administration of NMDA receptor antagonists (e.g., MK-801) during withdrawal can attenuate ethanol’s teratogenic effects. The aim of this study was to determine whether administration of memantine, an NMDA receptor antagonist, during ethanol withdrawal could effectively attenuate ethanol-related deficits, without the adverse side effects associated with other NMDA receptor antagonists. Methods: Sprague–Dawley pups were exposed to 6.0 g ⁄ kg ethanol or isocaloric maltose solution via intubation on postnatal day 6, a period of brain development equivalent to a portion of the 3rd trimester. Twenty-four and 36 hours after ethanol, subjects were injected with 0, 10, or 15 mg ⁄ kg memantine, totaling doses of 0, 20, or 30 mg ⁄ kg. Motor coordination was tested on a parallel bar task and the total number of cerebellar Purkinje cells was estimated using unbiased stereology. Results: Alcohol exposure induced significant parallel bar motor incoordination and reduced Purkinje cell number. Memantine administration significantly attenuated both ethanol-associated motor deficits and cerebellar cell loss in a dose-dependent manner. Conclusions: Memantine was neuroprotective when administered during ethanol withdrawal. These data provide further support that ethanol withdrawal contributes to fetal alcohol spectrum

BACKGROUND Prenatal alcohol exposure can alter physical and behavioral development, leading to a range of fetal alcohol spectrum disorders (FASD). Despite warning labels, pregnant women continue to drink alcohol, creating a need to identify effective interventions to reduce the severity of alcohol’s teratogenic effects. Choline is an essential nutrient that influences brain and behavioral development. Recent studies indicate that choline supplementation can reduce the teratogenic effects of developmental alcohol exposure. The present study examined whether choline supplementation during prenatal ethanol treatment could mitigate the adverse effects of ethanol on behavioral development.

The present experiment assessed motor response programming and movement time in children with histories of heavy prenatal alcohol exposure. Alcohol-exposed children between the ages of 7 and 17 years were classified into two groups: Fetal Alcohol Syndrome (FAS: n = 9) and children with prenatal alcohol exposure (PEA: n = 19) but who did not have the defining characteristics of FAS. The FAS and PEA children were compared to non-alcohol exposed children (NC: n = 23) when completing two tasks: a simple reaction time task (RT alone condition) and a reaction plus movement task (RT + Move condition). The movement involved responding to an imperative stimulus signal and depressing three target buttons in a set sequence. Participants completed 24 trials each for the RT alone and RT + Move response conditions. Results indicated no significant differences in performance among FAS, PEA and NC groups during the RT alone condition. However, during the RT + Move condition, the FAS group produced significantly longer and more variable reaction times than either the PEA and NC groups, which produced comparable reaction times. The FAS group also produced significantly slower movement times when moving to all three targets, whereas movement time variability did not significantly differ as a function of group. The observed results indicate children with FAS experience deficits in response programming and movement time production.

The annual meeting of the Fetal Alcohol Spectrum Disorders Study Group (FASDSG) was held on June 28, 2008 in Washington DC, as a satellite to the Research Society on Alcoholism meeting. The FASDSG membership includes clinical, basic and social scientists, who meet to discuss recent advances and issues in FASD research. The main theme of the meeting was “Factors that Influence Brain and Behavioral Development: Implications for Prevention and Intervention.” Two keynote speakers, Dr. Stephen Suomi and Dr. Carl Keen addressed how early environment and nutrition may influence outcome following prenatal alcohol exposure. The final keynote speaker, Kathy Mitchell, addressed issues regarding the relationship between scientists and the families with children with FASD. Members of the FASDSG provided updates on new findings through brief (FASt) data reports, and national agency representative provided updates of activities and funding priorities. Presentations were also made by recipients of the Student Research Merit award and Rosett award.

Children exposed to alcohol prenatally may suffer from severe brain damage, expressed as a variety of behavioral problems, including hyperactivity and learning deficits. There is a critical need to identify effective treatments for fetal alcohol effects. Physical exercise enhances cognitive ability and increases neurogenesis in the hippocampus, a brain area important for learning and memory. Thus, the present study examined whether physical exercise might reduce the severity of alcohol-induced behavioral alterations. Sprague-Dawley rats were intubated with 5.25 g/kg/day ethanol during the third trimester equivalent (postnatal days [PDs] 4-9). Intubated sham control and nontreated controls were included. From PD 21 to PD 51, half of the subjects were given access to running wheels. On PD 52, subjects were tested on the Morris water maze, and on PD 60, open field activity levels were measured. Morris maze performance was significantly impaired among ethanol-exposed subjects; exercise significantly improved performance of all groups. Similarly, ethanol-exposed subjects were overactive in the open field, an effect attenuated with exercise. In sum, these data suggest that exercise may increase neuronal plasticity not only in controls, but also in subjects exposed to alcohol during development.

Among studies with continuous outcomes in our systematic review comparing placebo effect sizes with treatment effect sizes we calculated mean differences between to estimate placebo effects, treatment effects, and the difference between placebo and treatment effects. In fact the standardized mean difference should have been used. There was no error in the calculations among studies with binary outcomes. We have corrected this error and revised Figs ​Figs3,3, ​,44 and ​and55 from our review here. Correcting the error strengthened our conclusion that there is rarely a statistically significant difference (at P = 0.05 or lower) between the magnitude of placebo effects and the magnitude of treatment effects. In the original review placebo effect sizes and treatment effect sizes did not differ by a statistically significant amount in the three subgroup analyses: all studies with objective outcomes (treatment effects larger), studies of anxiety treatments (treatment effects larger), and studies where all criteria for ruling out bias were met (placebo effects larger). Fig 3 Placebo versus treatment effects (continuous outcomes) Fig 4 Conditions tested in three or more trials (continuous outcomes) Fig 5 Trials with varying degrees of bias (continuous outcomes) Our corrected analysis revealed no statistically significant difference between placebo effect sizes and treatment effect sizes in all but two subgroup analyses, and in both of them placebo effects were larger. These were: all studies that reported clear allocation concealment, and studies where all criteria for bias ruled out (placebo effects larger). Since placebo effects appear to be relatively greater when bias is ruled out, our corrected conclusions also reduce the possibility that placebo effects are attributable to bias. It is important to note that the placebo and treatment effects may not be independent. For example large placebo effects could be correlated with small treatment effects. Hence there is currently no perfect statistical solution to the problem of comparing effects of placebos and treatments within three-armed trials (no treatment, placebo, treatment). However using the within study difference in effects (placebo effect–treatment effect) and an estimate of the standard deviation of this comparison based on assuming (perhaps incorrectly) independence between effects, allows the use of the standardized mean difference to obtain a pooled estimate of the difference between these two effects. Professor Stephen Senn assisted with the analysis that allowed us to recalculate the differences between placebo and treatment effects in this Erratum.