Developmental Trajectories for Visuo-Spatial Attention are Altered by Prenatal Alcohol Exposure: A Longitudinal FMRI Study.

Functional magnetic resonance imaging (fMRI) reveals brain activation abnormalities during visuo-spatial attention and working memory among those with fetal alcohol spectrum disorders (FASD) in cross-sectional reports, but little is known about how activation changes over time during development within FASD or typically developing children. We studied 30 controls and 31 individuals with FASD over 2 years (7-14 years at first participation) with a total of 122 scans, as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders. Despite comparable performance, there were significant group differences in visuo-spatial activation over time bilaterally in frontal, parietal, and temporal regions. Controls showed an increase in signal intensity in these multiple regions whereas FASD participants showed a decrease in brain activation. Effects were also found in 2 small independent samples from the USA, corroborating the findings from the larger group. Results suggest that the long-lasting effect of prenatal alcohol may impact the maturation of visuo-spatial attention and differentiate those with FASD from controls. Based on this first longitudinal fMRI study in FASD children, our novel findings suggest a possible neural mechanism for attention deficits common among individuals with FASD.

Field primatology of today: current ethical issues.

As members of professional organizations such as American Society of Primatologists (ASP) and the International Primatological Society (IPS), primatologists must adhere to a set of nonhuman primate-focused principles outlined in resolutions and policy statements on, for example, the ethical treatment of nonhuman primates. Those of us that work in the field must also address issues such as the protection of primate health in the wild and the conservation of wild primate populations. Moreover, we increasingly find ourselves in complex situations where we must balance human and nonhuman primate needs and interests. The selection of commentary pieces in this edition of the American Journal of Primatology originated from presentations given in the symposium, Field Primatology of Today: Navigating the Ethical Landscape, held at the 32nd Annual Meeting of the American Society of Primatologists (ASP) in September 2009. The goals of that symposium and these resulting commentary pieces are threefold: (1) to revive a discussion of key contemporary ethical issues faced by field primatologists, (2) to highlight the need for centrally placed ethical considerations in various facets of our professional lives, particularly research and teaching, and (3) to consider what a comprehensive ethical code that addresses all of these issues might look like.

Prenatal alcohol exposure alters the patterns of facial asymmetry.

Directional asymmetry, the systematic differences between the left and right body sides, is widespread in human populations. Changes in directional asymmetry are associated with various disorders that affect craniofacial development. Because facial dysmorphology is a key criterion for diagnosing fetal alcohol syndrome (FAS), the question arises whether in utero alcohol exposure alters directional asymmetry in the face. Data on the relative position of 17 morphologic landmarks were obtained from facial scans of children who were classified as either FAS or control. Shape data obtained from the landmarks were analyzed with the methods of geometric morphometrics. Our analyses showed significant directional asymmetry of facial shape, consisting primarily of a shift of midline landmarks to the right and a displacement of the landmarks around the eyes to the left. The asymmetry of FAS and control groups differed significantly and average directional asymmetry was increased in those individuals exposed to alcohol in utero. These results suggest that the developmental consequences of fetal alcohol exposure affect a wide range of craniofacial features in addition to those generally recognized and used for diagnosis of FAS.

Chromosomal microarray mapping suggests a role for BSX and Neurogranin in neurocognitive and behavioral defects in the 11q terminal deletion disorder (Jacobsen syndrome).

We performed a prospective analysis on 14 11q- patients to determine the relationship between the degree of cognitive impairment and relative deletion size. Seventeen measures of cognitive function were assessed. All nine patients with a deletion of at least 12.1 Mb had severe global cognitive impairment, with full-scale IQ <50, whereas all five patients with smaller deletions,

Administration of eliprodil during ethanol withdrawal in the neonatal rat attenuates ethanol-induced learning deficits.

RATIONALE: Prenatal exposure to alcohol can disrupt brain development, leading to a variety of behavioral alterations, including learning deficits. We have postulated that some central nervous system damage may be due to N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity that occurs during ethanol withdrawal. Consistent with this hypothesis, we previously demonstrated that administration of MK-801, an NMDA receptor antagonist, during ethanol withdrawal attenuates ethanol-related learning deficits using an animal model of fetal alcohol effects. However, MK-801 binds to the phencyclidine site, which affects all NMDA receptor subtypes and can cause adverse side effects and toxicity. Eliprodil is a more selective NMDA receptor antagonist that acts at the polyamine modulatory site of NMDA receptors. OBJECTIVES: The purpose of this study was to determine if administration of eliprodil during ethanol withdrawal would reduce the severity of learning deficits associated with developmental alcohol exposure. METHODS: Male rat pups were randomly assigned to ethanol-exposed or control treatments. On postnatal day (PD) 6, during a period of brain development similar to that of the mid-third trimester in humans, subjects were exposed to 6.0 g/kg ethanol or isocaloric maltose solutions via oral gavage. Twenty-four hours after the end of the ethanol treatment, during ethanol withdrawal, all subjects received an intraperitoneal injection of one of three doses of eliprodil (5, 10, or 25 mg/kg) or vehicle. On PD 40, all subjects were tested on a serial spatial discrimination reversal learning task. RESULTS: Ethanol-exposed subjects treated with vehicle committed a significantly greater number of errors compared to controls. Administration of eliprodil during ethanol withdrawal significantly decreased the number of errors in the ethanol-exposed groups, but had no significant effect on the performance of controls. CONCLUSION: These data support the hypothesis that NMDA receptor-mediated excitotoxicity during ethanol withdrawal contributes to fetal alcohol effects.

Differential vulnerability to motor deficits in second replicate HAS and LAS rats following neonatal alcohol exposure.

Children exposed prenatally to alcohol suffer from a variety of behavioral alterations. However, variation exists in the pattern and severity of these alcohol-related neurodevelopmental disorders. We examined the influence of alcohol sensitivity in the etiology of fetal alcohol effects by studying rat lines selectively bred for extremes in alcohol-induced sleep time: high-alcohol-sensitive (HAS) and low-alcohol-sensitive (LAS) rats. Using subjects from the first replicate, we previously reported that HAS rats exposed to alcohol during development were more vulnerable to ethanol-induced hyperactivity and motor deficits compared to LAS rats. To determine if these effects were, in fact, related to the trait for which these subjects were selected, the present study examined the consequences of developmental alcohol exposure in second replicate HAS and LAS rats. Second replicate HAS and LAS rats, as well as Sprague-Dawley rats, were exposed to 6.0 g/kg/day ethanol on Postnatal Days (PD) 4-9, a period of brain development equivalent to the third trimester, via an artificial rearing procedure. Artificially and normally reared controls were included. Activity was measured on PD 18-21 and parallel bar motor coordination on PD 30-32. Ethanol exposure produced hyperactivity in all genetic groups, and there were no differences among HAS and LAS rats. In contrast, consistent with findings from the first replicate, ethanol-exposed HAS rats were more impaired on the motor coordination task compared with LAS rats. These data suggest that genetically mediated responses to alcohol may relate to behavioral vulnerability to motor deficits following developmental alcohol exposure. They also provide evidence that genetic factors play a role in fetal alcohol effects and suggest that phenotypic markers may indicate individuals at high risk for some fetal alcohol effects.

Administration of low doses of MK-801 during ethanol withdrawal in the developing rat pup attenuates alcohol's teratogenic effects.

BACKGROUND: Alcohol exposure during development can produce severe and long-lasting central nervous system damage and consequent behavioral alterations. Recent evidence suggests that NMDA receptor-mediated excitotoxicity during periods of withdrawal may contribute to this damage. We have demonstrated that blocking the NMDA receptor with MK-801 during alcohol withdrawal can attenuate ethanol's adverse effects on behavioral development in the rat. This study examined the dose dependency of MK-801's ability to mitigate ethanol's teratogenic effects. METHODS: Neonatal rat pups were exposed to 6.0 g/kg of ethanol in a binge-like manner on postnatal day (PD) 6, a period of brain development equivalent to a portion of the human third trimester. Alcohol administration was accomplished with an artificial rearing procedure. Twenty-one hours after ethanol treatment, pups were injected intraperitoneally with one of four doses of MK-801 (0.05, 0.1, 0.5, or 1.0 mg/kg) or saline vehicle. An artificially reared control and a normally reared control group were included. On PD 18-19, activity level was monitored, and on PD 40-42, serial spatial discrimination reversal learning was assessed. RESULTS: Alcohol exposure on PD 6 produced significant increases in activity level and deficits in reversal learning. These alcohol-induced behavioral alterations were significantly attenuated in subjects treated with one of the three lower doses (0.05-0.5 mg/kg) of MK-801 during withdrawal. The performance of ethanol-exposed subjects treated with the high dose of MK-801 (1.0 mg/kg) did not differ from that of the Ethanol Only group. CONCLUSIONS: These data suggest that alterations in NMDA receptor activation during alcohol withdrawal contribute to the neuropathology and consequent behavioral alterations associated with developmental alcohol exposure. These data have important implications for pregnant women and newborns undergoing ethanol withdrawal.

Early maternal separation alters neuropeptide Y concentrations in selected brain regions in adult rats.

Human and animal studies support the involvement of neuropeptide Y (NPY) in the pathophysiology of depression. Thus, hippocampal NPY-LI is decreased in genetic models of depression, the Flinders Sensitive Line and Fawn Hooded rats. Maternal "deprivation" has been identified as one risk factor in the development of psychopathology, including depression in adulthood. In view of these findings we hypothesized that brain NPY may also be decreased in an animal model of early life maternal deprivation. To test this hypothesis, male and female Sprague-Dawley rats were maternally separated (MS) 6 h/day or briefly handled from postnatal day 2 (PN2) to PN6 and from PN9 to PN13. At 12 weeks of age the rats were sacrificed, the brains dissected and NPY-LI measured by radioimmunoassay. MS rats had lower NPY-LI in the hippocampus. NPY-LI was also lower in female compared to male rats in hippocampus. Lastly, NPY-LI was increased in the hypothalamus of both male and female MS rats. These findings support the hypothesis that altered NPY in the limbic region is a common denominator of several models of depression and might be a trait marker of vulnerability to affective disorders.

Mapping callosal morphology and cognitive correlates: effects of heavy prenatal alcohol exposure.

BACKGROUND: Abnormalities of the corpus callosum (CC) have been documented in fetal alcohol syndrome (FAS), ranging from subtle decrements in its size to partial and even complete agenesis. Prenatal exposure to alcohol is also known to result in neurocognitive deficits. OBJECTIVE: To 1) investigate abnormalities in size, shape, and location of the CC within the brain in individuals with FAS and in those exposed to high amounts of alcohol prenatally but without FAS (PEA group); and 2) determine if there is a relationship between callosal dysmorphology and cognitive test performance. METHODS: MRI and novel surface-based image analytic methods were used. Twenty alcohol-exposed subjects (8 to 22 years) along with 21 normal controls (8 to 25 years) were studied with high-resolution MRI and measures of verbal learning and visuospatial abilities. RESULTS: In addition to callosal area reductions, most severe in the splenium, the CC is significantly displaced in patients exposed to alcohol prenatally. In the alcohol-exposed group, this structure lies more anterior and inferior in posterior regions with relatively normal localization of anterior regions. These findings are significant in the FAS group, and a similar but less severe pattern is observed in the PEA patients. The authors show that the amount of CC displacement is correlated with impairment in verbal learning ability and that CC displacement is a better predictor of verbal learning than regional CC area. The brain-behavior relationship is only significant within the alcohol-exposed group, and the effect is not solely mediated by overall impaired verbal intellectual functioning. CONCLUSIONS: These results further emphasize the vulnerability of midline brain structures to prenatal alcohol exposure.

Fetal alcohol effects: mechanisms and treatment.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Edward P. Riley. The presentations were (1) Does alcohol withdrawal contribute to fetal alcohol effects? by Jennifer D. Thomas and Edward P. Riley; (2) Brain damage and neuroplasticity in an animal model of binge alcohol exposure during the "third trimester equivalent," by Charles R. Goodlett, Anna Y. Klintsova, and William T. Greenough; (3) Ganglioside GM1 reduces fetal alcohol effects, by Basalingappa L. Hungund; and (4) Fetal alcohol exposure alters the wiring of serotonin system at mid-gestation, by F. Zhou, Y. Sari, Charles Goodlett, T. Powrozek, and Ting-Kai Li.

Verbal and nonverbal fluency in children with heavy prenatal alcohol exposure.

OBJECTIVE: Executive function deficits, including verbal fluency, have been documented in children with histories of prenatal alcohol exposure. Whereas nonverbal fluency impairments have been reported in adults with such exposure, these abilities have not been tested in children. Deficits in both verbal and nonverbal fluency were predicted and assessed in children and adolescents with histories of heavy prenatal alcohol exposure. METHOD: There was a total of 28 (54% female) subjects; children with heavy prenatal alcohol exposure with (n = 10) and without (n = 8) fetal alcohol syndrome (FAS) were compared to nonexposed controls (n = 10) on the design and verbal fluency measures from the Delis-Kaplan Executive Function System. Both fluency measures consist of three conditions, including a new set-shifting task. All tests require the generation of multiple responses within both rule and time constraints. RESULTS: Data were analyzed using repeated measures analyses of variance and hierarchical regression analyses. Compared to controls, children with heavy prenatal alcohol exposure with and without FAS displayed deficits in both fluency domains, but did not differ from each other. In addition, prenatal alcohol exposure was a significant predictor of performance on the set-shifting design fluency task above and beyond performance on more traditional fluency tasks. IQ was not a significant predictor for the traditional or set-shifting fluency measures, whereas diagnostic group remained a significant predictor when IQ was included in the model. CONCLUSIONS: This study adds to the literature on the integrity of executive functions in children with heavy prenatal alcohol exposure, documenting fluency impairment in both verbal and nonverbal domains. It is important to note that these impairments were demonstrated in higher functioning alcohol-exposed children, both with and without FAS, and that diagnostic group explained such deficiencies above and beyond general intellectual ability.

MK-801 can exacerbate or attenuate behavioral alterations associated with neonatal alcohol exposure in the rat, depending on the timing of administration.

BACKGROUND: We have reported that administration of MK-801, an NMDA receptor antagonist, during ethanol withdrawal in the developing rat attenuates ethanol's adverse effects on behavioral development. In the present study, we altered the timing of MK-801 delivery in relation to the last alcohol dose to determine if its protective effects were specific to the ethanol withdrawal phase. METHODS: Five groups of rats were artificially reared and exposed to alcohol in a binge-like manner on postnatal day (PD) 6, producing peak blood alcohol levels of 335 mg/dl that cleared to 0 mg/dl by 33 hours. Four groups received MK-801 at various times after alcohol treatment (0, 9, 21, or 33 hr post-ethanol). The fifth alcohol-treated group received saline. Two artificially reared control groups were included: one was injected with saline and the other injected with 0.5 mg/kg MK-801. Finally, a normally reared suckle control group was also included. Activity level and performance on a spatial discrimination reversal-learning task were evaluated at PD 18 and PD 40, respectively. RESULTS: Administration of MK-801 at the same time as ethanol treatment (0 hr) produced a high rate of mortality. Ethanol exposure on PD6 increased activity level relative to controls. Administration of MK-801 at 0 hr exacerbated this ethanol-induced overactivity, whereas administration of MK-801 at 21 and 33 hr reduced the severity of ethanol-related overactivity. Similarly, ethanol exposure on PD 6 significantly increased the number of errors committed on a spatial discrimination reversal-learning task. MK-801 injections 9 hrs after ethanol exacerbated this effect, whereas MK-801 treatment 33 hrs after ethanol attenuated this effect. Thus, MK-801 administration at the time of ethanol treatment was highly toxic, whereas during the withdrawal period it was protective. CONCLUSION: These data are consistent with the hypothesis that ethanol exposure in the neonatal rat inhibits the NMDA receptor, producing a subsequent rebound in NMDA receptor activation and possible excitotoxicity during withdrawal. Both the acute inhibitory effects of ethanol and the excitatory effects of withdrawal may contribute to fetal alcohol effects.

Brain dysmorphology in individuals with severe prenatal alcohol exposure.

Our previous studies revealed abnormalities on structural MRI (sMRI) in small groups of children exposed to alcohol prenatally. Microcephaly, disproportionately reduced basal ganglia volume, and abnormalities of the cerebellar vermis and corpus callosum were demonstrated. The present study used sMRI to examine in detail the regional pattern of brain hypoplasia resulting from prenatal exposure to alcohol using a higher resolution imaging protocol and larger sample sizes than reported previously. Fourteen participants (mean 11.4 years; eight females, six males) with fetal alcohol syndrome (FAS) and 12 participants (mean 14.8 years; four females, eight males) with prenatal exposure to alcohol (PEA) but without the facial features of FAS were compared to a group of 41 control participants (mean 12.8 years, 20 females, 21 males). Findings of significant microcephaly and disproportionately reduced basal ganglia volumes in the FAS group were confirmed. Novel findings were that in FAS participants, white matter volumes were more affected than gray matter volumes in the cerebrum, and parietal lobes were more affected than temporal and occipital lobes. Among subcortical structures, in contrast to the disproportionate effects on caudate nucleus, the hippocampus was relatively preserved in FAS participants. Differences between the PEA group and controls were generally non-significant; however, among a few of the structures most affected in FAS participants, there was some evidence for volume reduction in PEA participants as well, specifically in basal ganglia and the parietal lobe. There were no group differences in cerebral volume asymmetries. Severe prenatal alcohol exposure appears to produce a specific pattern of brain hypoplasia.

Voxel-based morphometric analyses of the brain in children and adolescents prenatally exposed to alcohol.

Children of mothers who abuse alcohol during pregnancy can suffer varying degrees of neurological abnormality, cognitive impairment, and behavioral problems, and in the worst case, are diagnosed with fetal alcohol syndrome (FAS). The purpose of the present study was to localize brain abnormalities in a group of children and adolescents prenatally exposed to alcohol using high resolution, 3D structural MRI data and whole-brain voxel-based morphometry (VBM). Data were collected for 21 children and adolescents with histories of prenatal alcohol exposure (ALC) and 21 normally developing individuals. Statistical parametric maps revealed abnormalities most prominent in the left hemisphere perisylvian cortices of the temporal and parietal lobes where the ALC patients tended to have too much gray matter and not enough white matter. These results provide further support for dysmorphology in temporo-parietal cortices above and beyond the overall microcephaly that results from severe prenatal alcohol exposure.

Teratogenic effects of alcohol on brain and behavior.

Children prenatally exposed to alcohol can suffer from serious cognitive deficits and behavioral problems as well as from alcohol-related changes in brain structure. Neuropsychological studies have identified deficits in learning and memory as well as in executive functioning both in children with fetal alcohol syndrome and in children with less severe impairments. Both groups of children also exhibit problem behaviors, such as alcohol and drug use, hyperactivity, impulsivity, and poor socialization and communication skills. Brain imaging studies have identified structural changes in various brain regions of these children--including the basal ganglia, corpus callosum, cerebellum, and hippocampus--that may account for the cognitive deficits. Functional brain imaging studies also have detected changes in alcohol-exposed children indicative of deficits in information processing and memory tasks.

Nicotine exposure during the neonatal brain growth spurt produces hyperactivity in preweanling rats.

Despite warning labels and increases in evidence of the adverse effects of tobacco use, women continue to use tobacco products during pregnancy. Cigarette smoking has been linked to increased prenatal mortality, increased incidence of SIDS, reductions in birth weight, and disruptions in CNS and behavioral development. Animal model systems have critically established the causal relationship between nicotine and adverse developmental outcome. The present study examines the behavioral effects of nicotine exposure in the rat during the third trimester equivalent of the human brain growth spurt, a period of rapid development of the cholinergic systems and a period during which the CNS is particularly vulnerable to a number of insults. Sprague-Dawley rat pups were exposed to nicotine (6.0 mg/kg/day) from postnatal days (PD) 4-9 via an artificial rearing procedure. This procedure ensures that observed effects are not due to nutritional deficits. Two control groups were employed, an artificially reared control group and a normally reared control group. Activity level was measured on PD 18-19. Nicotine-exposed subjects were significantly overactive compared to both control groups, which did not differ significantly from one another. This behavioral alteration was observed in the absence of nicotine-induced body weight deficits. These results suggest that women who use tobacco products during late gestation may place their fetuses at risk for hyperactivity later in life, particularly during early adolescence.

Neonatal choline supplementation ameliorates the effects of prenatal alcohol exposure on a discrimination learning task in rats.

Prenatal alcohol exposure can disrupt brain development and lead to a myriad of behavioral alterations, including motor coordination deficits, hyperactivity, and learning deficits. There remains a need, however, to identify treatments and interventions for reducing the severity of alcohol-related neurodevelopmental disorders. Some of the alcohol-induced deficits in learning may be related to alterations in cholinergic functioning. Interestingly, there is a growing literature demonstrating that pre- and/or early postnatal choline supplementation can lead to long-term enhancement in learning and memory and cholinergic activity in rats. The present study examined whether such early choline supplementation might counter the effects of prenatal alcohol treatment on a visuospatial discrimination task. Pregnant Sprague-Dawley rats were randomly assigned to one of three prenatal treatment groups. One group received a liquid diet containing 35% ethanol-derived calories (EDC) from gestational day (GD) 6-20. A second group served as a pair-fed (PF) control group and the third group served as an ad lib lab chow (LC) control. On postnatal day (PD) 2, pups were assigned within-litter to one of three postnatal treatments: choline, saline vehicle, or no treatment. Choline and vehicle pups were intubated with a choline chloride solution or vehicle daily from PD 2 to 21, whereas the non-treated pups were handled daily but not intubated. On PD 45, subjects were tested on a visuospatial discrimination task. Ethanol-exposed subjects who were not treated neonatally with choline committed a significantly greater number of errors both during acquisition and during delayed discrimination training compared to both PF and LC controls. Neonatal choline treatment significantly improved performance on the discrimination task in all groups; however, the beneficial effects of choline were significantly larger in ethanol-exposed subjects. Indeed, the performance of ethanol-exposed pups treated with neonatal choline did not differ from any of the PF or LC groups on any measure. Thus, early postnatal choline supplementation significantly attenuated the effects of prenatal alcohol on this learning task. Importantly, these effects were not due to the acute effects of choline, but rather to long-term changes in brain and behavioral development. These data suggest that early dietary interventions may reduce the severity of fetal alcohol effects.

Neonatal nicotine exposure alters hippocampal EEG and event-related potentials (ERPs) in rats.

A consensus is forming that nicotine can damage the developing rat central nervous system. However, few studies have assessed the electrophysiological effects of neonatal nicotine exposure in rodents in brain regions known to be sensitive to the teratogenic properties of nicotine. In a previous study it was reported that 1.0 and 4.0 mg/kg/day nicotine exposure from postnatal days 4-9, a developmental period corresponding to human third-trimester exposure, significantly altered hippocampal event-related potentials (ERPs) but did not effect cortical ERPs, cortical EEG, or hippocampal EEG. Because alterations in behavior and cortical/hippocampal neurochemistry and morphology have been reported following nicotine exposure, the present study used a higher dose of nicotine during the postnatal period (6.0 mg/kg/day) determine if functional changes in the EEG of these regions might contribute to behavioral changes that have been observed. Male Sprague-Dawley rats were exposed to 6. 0 mg/kg/day nicotine via gastric infusion using an artificial rearing, "pup-in-the-cup," technique for 6 consecutive days (postnatal days 4-9). At adulthood, EEG and auditory ERPs were recorded from the cortex and hippocampus. There were no significant differences in EEG or ERPs recorded from the cortex between nicotine-treated and control subjects. Examination of the hippocampal EEG revealed significantly decreased power in the 1-2-Hz frequency band of nicotine-treated rats. In addition, there was a significantly attenuated P300 ERP response to a noise tone in the nicotine-treated rats compared to controls. These data indicate that neonatal nicotine exposure alters functional activity in the hippocampus of adult rats. These effects are likely to be the result of synaptic disorganization in the hippocampus, and indicate that neonatal nicotine exposure exerts teratogenic effects on the developing central nervous system, particularly the hippocampus, which persist into adulthood.