63 results
Search Results
2. Fetal Alcohol Spectrum Disorders: A Review of the Neurobehavioral Deficits Associated With Prenatal Alcohol Exposure.
- Author
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Mattson, Sarah N., Bernes, Gemma A., and Doyle, Lauren R.
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ACADEMIC achievement ,FETAL alcohol syndrome ,CHILD development ,INTELLECT ,LANGUAGE acquisition ,LEARNING ,MEMORY ,NEUROLOGIC manifestations of general diseases ,EXECUTIVE function ,PRENATAL exposure delayed effects ,DISEASE complications ,DISEASE risk factors - Abstract
In utero alcohol exposure can disrupt the development of the fetal brain and result in a wide range of neurobehavioral outcomes collectively known as fetal alcohol spectrum disorders (FASD). This paper provides a comprehensive review of the cognitive and behavioral outcomes of prenatal alcohol exposure, including domains of general intelligence, executive functioning, language development, learning and memory, adaptive functioning, academic performance, and concurrent psychopathology. In addition, the current status of the neurobehavioral profile of FASD and its potential as a diagnostic tool will be discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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3. Genetic Absence of nNOS Worsens Fetal Alcohol Effects in Mice. II: Microencephaly and Neuronal Losses.
- Author
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Karacay, Bahri, Mahoney, Jo, Plume, Jeffrey, and Bonthius, Daniel J.
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FETAL alcohol syndrome ,ANALYSIS of variance ,ANIMAL experimentation ,BRAIN ,STATISTICAL correlation ,ETHANOL ,MICE ,MULTIVARIATE analysis ,GENETIC mutation ,OXIDOREDUCTASES ,RESEARCH funding ,STATISTICAL sampling ,STATISTICS ,DATA analysis ,DATA analysis software ,DESCRIPTIVE statistics ,GENOTYPES ,DISEASE complications - Abstract
Background Prenatal alcohol exposure can kill developing neurons, leading to microencephaly and mental retardation. However, not all fetuses are equally vulnerable to alcohol's neurotoxic effects. While some fetuses are severely affected and are ultimately diagnosed with fetal alcohol syndrome (FAS), others have no evidence of neuropathology and are behaviorally normal. These widely different outcomes among alcohol-exposed fetuses are likely due, in part, to genetic differences. Some fetuses possess genotypes that make them much more vulnerable than others to alcohol's teratogenic effects. However, to date, only 1 gene has been identified whose mutation can worsen alcohol-induced behavioral deficits in an animal model of FAS. That gene is neuronal nitric oxide synthase ( nNOS). The purpose of this study was to determine whether mutation of nNOS can likewise worsen alcohol-induced microencephaly and lead to permanent neuronal deficits. Methods Wild-type and nNOS
−/− mice received alcohol (0.0, 2.2, or 4.4 mg/g) daily over postnatal days (PDs) 4 to 9. Beginning on PD 85, the mice underwent a series of behavioral tests; the results of which are reported in the companion paper. The brains were then weighed, and stereological cell counts were performed on the cerebral cortex and hippocampal formation, which are the brain regions that mediate the aforementioned behavioral tasks. Results Alcohol caused dose-dependent microencephaly, but only in the nNOS−/− mice and not in wild-type mice. Alcohol-induced neuronal losses were more severe in the nNOS−/− mice than in the wild-type mice in all of the brain regions examined, including the cerebral cortex, hippocampal CA3 subregion, hippocampal CA1 subregion, and dentate gyrus. Conclusions Targeted mutation of the nNOS gene increases the vulnerability of the developing brain to alcohol-induced growth restriction and neuronal losses. This increased neuropathology is associated with worsened behavioral dysfunction. The results demonstrate the critical importance of genotype in determining the outcome of developmental alcohol exposure. [ABSTRACT FROM AUTHOR]- Published
- 2015
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4. Alcohol and the Human Brain: A Systematic Review of Different Neuroimaging Methods.
- Author
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Bühler, Mira and Mann, Karl
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ALCOHOLISM treatment ,RADIOGRAPHY ,DISEASE relapse ,MAGNETIC resonance imaging ,NEURORADIOLOGY ,BRAIN diseases ,ALCOHOLISM ,BLOOD sugar ,BRAIN ,COGNITION disorders ,ALCOHOL drinking ,ETHANOL ,FRONTAL lobe ,GLUCOSE ,HUMAN information processing ,PSYCHOLOGY information storage & retrieval systems ,MEDLINE ,METABOLIC disorders ,NEUROTRANSMITTERS ,NUCLEAR magnetic resonance spectroscopy ,ONLINE information services ,RESEARCH funding ,TELENCEPHALON ,TOMOGRAPHY ,POSITRON emission tomography ,WERNICKE'S encephalopathy ,SYSTEMATIC reviews ,SINGLE-photon emission computed tomography - Abstract
Background: Imaging techniques have been in widespread use in the scientific community for more than 3 decades. They facilitate noninvasive, in vivo studies of the human brain in both healthy and diseased persons. These brain-imaging techniques have contributed significantly to our understanding of the effects of alcohol abuse and dependence on structural and functional changes in the human brain. A systematic review summarizing these contributions has not previously been conducted, and this is the goal of the current paper. Methods: The databases PubMed, PsycINFO, and PSYNDEX were searched using central key words. Fulfilling the inclusion criteria were 140 functional and structural imaging studies, together comprising data from more than 7,000 patients and controls. The structural imaging techniques we considered were cranial computerized tomography and various magnetic resonance imaging-based techniques, including voxel-based morphometry, deformation-based morphometry, diffusion tensor magnetic resonance imaging, and diffusion-weighted magnetic resonance imaging. The functional methods considered were magnetic resonance spectroscopy, positron emission tomography, single photon emission computed tomography, and functional magnetic resonance imaging. Results: Results from studies using structural imaging techniques have revealed that chronic alcohol use is accompanied by volume reductions of gray and white matter, as well as microstructural disruption of various white matter tracts. These changes are partially reversible following abstinence. Results from functional imaging methods have revealed metabolic changes in the brain, lower glucose metabolism, and disruptions of the balance of neurotransmitter systems. Additionally, functional imaging methods have revealed increased brain activity in the mesocorticolimbic system in response to alcohol-themed pictures relative to nondrug-associated stimuli, which might be of predictive value with regard to relapse. Conclusions: There has been tremendous progress in the development of imaging technologies. Use of these technologies has clearly demonstrated the structural and functional brain abnormalities that can occur with chronic alcohol use. The study of the alcoholic brain provides an heuristic model which furthers our understanding of neurodegenerative changes in general, as well as their partial reversibility with sustained abstinence. Additionally, functional imaging is poised to become an important tool for generating predictions about individual brain functioning, which can then be used as a basis for personalized medicine. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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5. Longitudinal Brain Magnetic Resonance Imaging Study of the Alcohol-Preferring Rat. Part II: Effects of Voluntary Chronic Alcohol Consumption.
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Pfefferbaum, Adolf, Adalsteinsson, Elfar, Sood, Rohit, Mayer, Dirk, Bell, Richard, McBride, William, Ting-Kai Li, and Sullivan, Edith V.
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ALCOHOL ,RATS ,MAGNETIC resonance imaging ,CORPUS callosum ,DRINKING (Physiology) ,BRAIN ,ALCOHOLISM ,PATHOLOGY ,BRAIN damage ,COHORT analysis - Abstract
Background: Tracking the dynamic course of human alcoholism brain pathology can be accomplished only through naturalistic study and without opportunity for experimental manipulation. Development of an animal model of alcohol-induced brain damage, in which animals consume large amounts of alcohol following cycles of alcohol access and deprivation and are examined regularly with neuroimaging methods, would enable hypothesis testing focused on the degree, nature, and factors resulting in alcohol-induced brain damage and the prospects for recovery or relapse. Methods: We report the results of longitudinal magnetic resonance imaging (MRI) studies of the effects of free-choice chronic alcohol intake on the brains of 2 cohorts of selectively bred alcohol-preferring (P) rats. In the companion paper, we described the MRI acquisition and analysis methods, delineation of brain regions, and growth patterns in total brain and selective structures of the control rats in the present study. Both cohorts were studied as adults for about 1 year and consumed high doses of alcohol for most of the study duration. The paradigm involved a 3-bottle choice with 0, 15 (or 20%), and 30% (or 40%) alcohol available in several different exposure schemes: continuous exposure, cycles of 2 weeks on followed by 2 weeks off alcohol, and binge drinking in the dark. Results: Brain structures of the adult P rats in both the alcohol-exposed and the water control conditions showed significant growth, which was attenuated in a few measures in the alcohol-exposed groups. The region with the greatest demonstrable effect was the corpus callosum, measured on midsagittal images. Conclusion: The P rats showed an age–alcohol interaction different from humans, in that normal growth in selective brain regions that continues in adult rats was retarded. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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6. A Review of the Neuroanatomical Findings in Children with Fetal Alcohol Syndrome or Prenatal Exposure to Alcohol.
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Roebuck, Tresa M., Mattson, Sarah N., and Riley, Edward P.
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Human and animal studies have clearly demonstrated that alcohol is both a physical and behavioral teratogen and that heavy prenatal alcohol exposure can lead to a distinct pattern of birth defects termed the fetal alcohol syndrome. Underlying the behavioral and cognitive anomalies seen in fetal alcohol syndrome are alterations in brain structure and/or function. This paper reviews the literature examining brain anomalies attributable to prenatal alcohol exposure, beginning with a survey of autopsy studies and leading up to current findings using magnetic resonance imaging and positron emission tomography studies. Autopsy reports clearly illustrate the wide and devastating influence alcohol has on the developing brain, although for the most part no specific pattern of brain malformation has been identified. More recent magnetic resonance imaging studies, particularly when combined with quantitative analysis, have indicated that specific brain areas-such as the basal ganglia, the corpus callo-sum, and parts of the cerebellum-might be especially susceptible to alcohol's teratogenic effects. Further studies using functional brain imaging techniques may provide even more information about the unique effects prenatal alcohol exposure has on the developing brain. Discovering specific areas of the brain that are affected by alcohol may allow clinicians and researchers to look for patterns of vulnerable regions in the brain, thereby helping in the future detection of children who are prenatally exposed to alcohol. [ABSTRACT FROM AUTHOR]
- Published
- 1998
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7. New Approaches to Research on the Long-Term Consequences of Prenatal Exposure to Alcohol.
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West, James R., Goodlett, Charles R., and Brandt, Joan P.
- Abstract
As the summary presentation of a symposium on prenatal alcohol-induced brain damage and long-term postnatal consequences, this paper proposes the establishment of two main research priorities-to begin to correlate long-term behavioral effects with alterations in underlying neural substrates, and to explore the mechanisms of neuroteratogenicity. To reach these goals, three objectives are described. First, animal and human research must become more interrelated. Second, experimental observations should be integrated into formal models that incorporate both neural structure and function. Third, researchers should choose well-defined dependent measures that are derived from models of brain function based on modern concepts of cognitive neuroscience. Examples of neuropsychological tests that may serve as the bases for structure/function relationships are presented. Incorporating these objectives into future research will facilitate understanding of the fundamental issues concerning prenatal alcohol exposure and will begin to provide the bases for rational intervention or treatment. [ABSTRACT FROM AUTHOR]
- Published
- 1990
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8. Primed for addiction: A critical review of the role of microglia in the neurodevelopmental consequences of adolescent alcohol drinking.
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Melbourne, Jennifer K., Chandler, Cassie M., Van Doorn, Catherine E., Bardo, Michael T., Pauly, James R., Peng, Hui, and Nixon, Kimberly
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BRAIN ,SUBSTANCE abuse ,ALCOHOLISM ,NEURAL development ,ADOLESCENT health ,ALCOHOL drinking ,NEUROGLIA - Abstract
Alcohol is one of the most widely used recreational substances worldwide, with drinking frequently initiated during adolescence. The developmental state of the adolescent brain makes it vulnerable to initiating alcohol use, often in high doses, and particularly susceptible to alcohol‐induced brain changes. Microglia, the brain parenchymal macrophages, have been implicated in mediating some of these effects, though the role that these cells play in the progression from alcohol drinking to dependence remains unclear. Microglia are uniquely positioned to sense and respond to central nervous system insult, and are now understood to exhibit innate immune memory, or "priming," altering their future functional responses based on prior exposures. In alcohol use disorders (AUDs), the role of microglia is debated. Whereas microglial activation can be pathogenic, contributing to neuroinflammation, tissue damage, and behavioral changes, or protective, it can also engage protective functions, providing support and mediating the resolution of damage. Understanding the role of microglia in adolescent AUDs is complicated by the fact that microglia are thought to be involved in developmental processes such as synaptic refinement and myelination, which underlie the functional maturation of multiple brain systems in adolescence. Thus, the role microglia play in the impact of alcohol use in adolescence is likely multifaceted. Long‐term sequelae may be due to a failure to recover from EtOH‐induced tissue damage, altered neurodevelopmental trajectories, and/or persistent changes to microglial responsivity and function. Here, we review critically the literature surrounding the effects of alcohol on microglia in models of adolescent alcohol misuse. We attempt to disentangle what is known about microglia from other neuroimmune effectors, to which we apply recent discoveries on the role of microglia in development and plasticity. Considered altogether, these studies challenge assumptions that proinflammatory microglia drive addiction. Alcohol priming microglia and thereby perturbing their homeostatic roles in neurodevelopment, especially during critical periods of plasticity such as adolescence, may have more serious implications for the neuropathogenesis of AUDs in adolescents. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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9. Maternal choline supplementation mitigates alcohol exposure effects on neonatal brain volumes.
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Warton, Fleur L., Molteno, Christopher D., Warton, Christopher M. R., Wintermark, Pia, Lindinger, Nadine M., Dodge, Neil C., Zöllei, Lilla, van der Kouwe, Andre J.W., Carter, R. Colin, Jacobson, Joseph L., Jacobson, Sandra W., and Meintjes, Ernesta M.
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BRAIN anatomy ,COMPLICATIONS of alcoholism ,BRAIN ,RECOGNITION (Psychology) ,INFANT development ,MEMORY in children ,TIME ,FUNCTIONAL status ,HEALTH outcome assessment ,MAGNETIC resonance imaging ,BRAIN mapping ,CHOLINE ,DIETARY supplements ,PRENATAL exposure delayed effects ,PLACEBOS ,NEUROPROTECTIVE agents ,DESCRIPTIVE statistics ,DATA analysis software ,STATISTICAL correlation ,CHILDREN ,PREGNANCY - Abstract
Background: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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10. Neural correlates of alcohol use disorder severity among nontreatment‐seeking heavy drinkers: An examination of the incentive salience and negative emotionality domains of the alcohol and addiction research domain criteria.
- Author
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Al‐Khalil, Kareem, Vakamudi, Kishore, Witkiewitz, Katie, and Claus, Eric D.
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BRAIN ,EXECUTIVE function ,PARIETAL lobe ,SUBSTANCE abuse ,ALCOHOLISM ,PSYCHOLOGY of alcoholism ,HIPPOCAMPUS (Brain) ,AFFECT (Psychology) ,OCCIPITAL lobe ,BASAL ganglia ,FUNCTIONAL connectivity ,MAGNETIC resonance imaging ,SEVERITY of illness index ,CEREBELLUM ,EMOTIONS ,AMYGDALOID body - Abstract
Background: The Alcohol and Addiction Research Domain Criteria (AARDoC) propose that alcohol use disorder is associated with neural dysfunction in three primary domains: incentive salience, negative emotionality, and executive function. Prior studies in heavy drinking samples have examined brain activation changes associated with alcohol and negative affect cues, representing the incentive salience and negative emotionality domains, respectively. Yet studies examining such cue‐induced changes in functional connectivity (FC) are relatively sparse. Methods: Nontreatment‐seeking heavy drinking adults (N = 149, 56.0% male, 48.6% non‐white, mean age 34.8 years (SD = 10.0)) underwent functional magnetic resonance imaging during presentation of alcohol, negative, and neutral pictures. We focused on FC changes involving the nucleus accumbens and amygdala in addition to activation and FC correlations with self‐reported AUD severity. Results: For alcohol cues versus neutral cues, we observed accumbens FC changes in the cerebellum and prefrontal cortex (PFC), and amygdala FC changes with occipital, parietal, and hippocampal regions. AUD severity correlated positively with activation in the cerebellum (p < 0.05), accumbens FC in the cingulate gyri, somatosensory gyri, and cerebellum (p < 0.05), and with amygdala FC in the PFC and inferior parietal lobule (p < 0.05) for alcohol cues versus neutral cues. For negative cues versus neutral cues, we observed accumbens FC changes in the lateral temporal, occipital, and parietal regions, and amygdala FC changes in the fusiform and lingual gyri (p < 0.05). Conclusions: The present findings provide empirical support for the AARDoC domains of incentive salience and negative emotionality and indicate that AUD severity is associated with salience and response control for reward cues. When covarying for differences in nonalcohol substance use and mood disorder diagnoses, AUD severity was also associated with emotional reactivity for negative cues. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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11. Cross‐Sectional Analysis of Spatial Working Memory Development in Children with Histories of Heavy Prenatal Alcohol Exposure.
- Author
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Moore, Eileen M., Glass, Leila, Infante, M. Alejandra, Coles, Claire D., Kable, Julie A., Jones, Kenneth L., Riley, Edward P., and Mattson, Sarah N.
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FETAL alcohol syndrome ,BRAIN ,COGNITION ,ALCOHOL drinking ,SHORT-term memory ,SPACE perception ,FETAL development ,CROSS-sectional method ,PRENATAL exposure delayed effects ,PREGNANCY - Abstract
Background: In children with prenatal alcohol exposure, spatial working memory is affected and brain regions important for spatial working memory performance exhibit atypical neurodevelopment. We therefore hypothesized that children with prenatal alcohol exposure may also have atypical development of spatial working memory ability. Methods: We examined the relation between spatial working memory and age using a cross‐sectional developmental trajectory approach in youth with and without histories of heavy prenatal alcohol exposure. The Cambridge Neuropsychological Test Automated Battery Spatial Working Memory subtest was administered to children 5.0 to 16.9 years old. Results: While the controls and children with prenatal alcohol exposure showed similar performance at younger ages, larger group differences were observed in older children. This effect was replicated in a separate sample. Conclusions: The atypical brain development that has previously been reported in children with heavy prenatal alcohol exposure may have clinically relevant implications for cognitive development; however, longitudinal cognitive analyses are needed. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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12. Prospective Study Examining the Effects of Extreme Drinking on Brain Structure in Emerging Adults.
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Hua, Jessica P. Y., Sher, Kenneth J., Boness, Cassandra L., Trela, Constantine J., McDowell, Yoanna E., Merrill, Anne M., Piasecki, Thomas M., and Kerns, John G.
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COMPLICATIONS of alcoholism ,BRAIN anatomy ,BRAIN ,LONGITUDINAL method ,MAGNETIC resonance imaging ,SPECIAL days ,UNDERGRADUATES ,DESCRIPTIVE statistics - Abstract
Background: Emerging adulthood is a critical neurodevelopment period in which extreme drinking has a potentially pronounced neurotoxic effect. Therefore, extreme drinking, even a single episode, could be particularly harmful to the developing brain's structure. Relatedly, heavy alcohol use in emerging adults has been associated with structural brain damage, especially in the corpus callosum. However, it is unclear whether and how much a single extreme drinking episode would affect brain morphometry. Methods: For the first time in the literature, the current study prospectively examined the impact of an extreme drinking episode (i.e., twenty‐first birthday celebration) on the brain morphometry of emerging adults immediately following their birthday celebration (n = 50) and approximately 5 weeks post–birthday celebration (n = 29). Results: We found evidence that a single extreme drinking episode was associated with structural changes immediately post–birthday celebration. Specifically, higher twenty‐first birthday estimated blood‐alcohol concentration was associated with decreased volume of the posterior and central corpus callosum immediately post–birthday celebration. This extreme drinking episode was not associated with further structural changes, or recovery, 5 weeks post–twenty‐first birthday celebration. Conclusions: Overall, results suggest that a single episode of heavy drinking in emerging adulthood may be associated with immediate structural changes of the corpus callosum. Thus, emerging adulthood, which is characterized by high rates of extreme drinking, could be a critical period for targeted prevention and intervention. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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13. Para‐limbic Structural Abnormalities Are Associated With Internalizing Symptoms in Children With Prenatal Alcohol Exposure.
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Krueger, Alyssa M., Roediger, Donovan J., Mueller, Bryon A., Boys, Christopher A., Hendrickson, Timothy J., Schumacher, Mariah J., Mattson, Sarah N., Jones, Kenneth L., Riley, Edward P., Lim, Kelvin O., and Wozniak, Jeffrey R.
- Subjects
BRAIN anatomy ,MENTAL depression risk factors ,FETAL alcohol syndrome ,ANXIETY ,LIMBIC system ,MAGNETIC resonance imaging ,QUESTIONNAIRES ,SUBSTANCE abuse in pregnancy ,DISEASE complications - Abstract
Background: Prenatal alcohol exposure (PAE) is associated with a variety of structural abnormalities in the brain, including several within the para‐limbic system. Children with PAE have higher rates of internalizing disorders, including depression and anxiety, which may be related to underlying limbic system anomalies. Methods: Children aged 8 to 16 with PAE (n = 41) or without PAE (n = 36) underwent an magnetic resonance imaging of the brain and parents completed behavioral questionnaires about their children. Semi‐automated procedures (FreeSurfer) were used to derive para‐limbic volumes from T1‐weighted anatomical images. Results: There were significant group differences (PAE vs. nonexposed controls) in the caudate, hippocampus, and the putamen; children with PAE had smaller volumes in these regions even after controlling for total intracranial volume. A trend‐level association was seen between caudate volume and internalizing symptoms in children with PAE; smaller caudate volumes (presumably reflecting less optimal neurodevelopment) were associated with higher levels of anxiety and depression symptoms in these children. Conclusions: Caudate structure may be disproportionately affected by PAE and may be associated with the later development of internalizing symptoms in those affected by PAE. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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14. Chronic Ethanol Exposure Disrupts Lactate and Glucose Homeostasis and Induces Dysfunction of the Astrocyte–Neuron Lactate Shuttle in the Brain.
- Author
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Lindberg, Daniel, Ho, Ada Man Choi, Peyton, Lee, and Choi, Doo‐Sup
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BLOOD sugar analysis ,GLUCOSE analysis ,GLUCOSE metabolism ,ANIMAL experimentation ,BRAIN ,CARRIER proteins ,ETHANOL ,GENE expression ,HOMEOSTASIS ,LACTATES ,MICE ,NEUROGLIA ,NEURONS - Abstract
Background: Impairment of monocarboxylate transporter (MCT)‐dependent astrocyte‐neuron lactate transfer disrupts long‐term memory and erases drug‐associated memories in mice. However, few studies have examined how drugs of abuse alter astrocyte‐neuron lactate transfer in neurocircuits related to addiction. This is particularly pertinent for ethanol (EtOH), which has been demonstrated to impair central nervious system (CNS) glucose uptake and significantly alter peripheral levels of glucose, lactate, acetate, and ketones. Methods: We subjected C57BL/6J mice to a chronic intermittent EtOH (CIE) exposure paradigm to investigate how chronic EtOH exposure alters the concentration of glucose and lactate within the serum and CNS during withdrawal. Next, we determine how chronic injections of lactate (1 g/kg, twice daily for 2 weeks) influence central and peripheral glucose and lactate concentrations. Finally, we determine how CIE and chronic lactate injection affect astrocyte‐neuron lactate transfer by analyzing the expression of MCTs. Results: Our results show that CIE induces lasting changes in CNS glucose and lactate concentrations, accompanied by increased expression of MCTs. Interestingly, although chronic lactate injection mimics the effect of EtOH on CNS metabolites, chronic lactate injection is not associated with increased expression of MCTs. Conclusion: CIE increases CNS concentrations of glucose and lactate and augments the expression of MCTs. Although we found that chronic lactate injection mimics EtOH‐induced increases in CNS lactate and glucose, lactate failed to alter the expression of MCTs. This suggests that although lactate may influence the homeostasis of bioenergetic molecules in the CNS, EtOH‐associated increases in lactate are not responsible for increased MCT expression. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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15. The Relationship Between Regional Cerebral Blood Flow Estimates and Alcohol Problems at 5‐Year Follow‐Up: The Role of Level of Response.
- Author
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Courtney, Kelly E., Infante, Maria Alejandra, Brown, Gregory G., Tapert, Susan F., Simmons, Alan N., Smith, Tom L., and Schuckit, Marc A.
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ALCOHOL-induced disorders ,AGE distribution ,BRAIN ,CEREBRAL circulation ,ALCOHOL drinking ,FRONTAL lobe ,NEURORADIOLOGY ,REGRESSION analysis ,SEX distribution ,PHENOTYPES ,NEURAL pathways ,DISEASE risk factors - Abstract
Background: Acute alcohol consumption is associated with temporarily increased regional cerebral blood flow (CBF). The extent of this increase appears to be moderated by individual differences in the level of response (LR) to alcohol's subjective effects. The low LR phenotype is a known risk factor for the development of alcohol problems. This study investigates how the low LR phenotype relates to the relationship between alcohol‐related changes in CBF and alcohol problems 5 years later. Methods: Young adults (ages 18 to 25) were selected based on their LR to alcohol and underwent a neuroimaging protocol including arterial spin labeling and functional scans. These participants were recontacted ~5 years later and assessed on alcohol outcomes. A final sample of 107 subjects (54 low and 53 high LR subjects) was included in the analyses. Whole‐brain analysis revealed 5 clusters of significant alcohol‐induced, versus placebo‐induced, CBF changes that were consistent with a previous report. Peak alcohol–placebo CBF response was extracted from these regions and, along with the LR group, submitted to a hierarchical linear regression predicting alcohol problems. Analyses controlled for age, sex, and baseline alcohol problems. Results: In the regression analysis, greater alcohol–placebo CBF difference in the right middle/superior/inferior frontal gyri and bilateral anterior cingulate gyri clusters predicted greater future alcohol problems for the low LR group, whereas this relationship was not found to be significant in the high LR group. Conclusions: This study demonstrates a clinically important relationship between CBF and future alcohol problems, particularly in individuals with a low LR phenotype. These initial results help to elucidate the neurobiological pathways involved in the development of alcohol use disorders for individuals with low LR. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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16. Role of the Dynorphin/Kappa Opioid Receptor System in the Motivational Effects of Ethanol.
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Anderson, Rachel I. and Becker, Howard C.
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AFFECT (Psychology) ,AFFECTIVE disorders ,ALCOHOLISM ,BRAIN ,ETHANOL ,MOTIVATION (Psychology) ,NEUROTRANSMITTER receptors ,OPIOID peptides ,REWARD (Psychology) ,PSYCHOLOGICAL stress ,ALCOHOL withdrawal syndrome ,ALCOHOL-induced disorders ,CHEMICAL inhibitors - Abstract
Evidence has demonstrated that dynorphin (DYN) and the kappa opioid receptor (KOR) system contribute to various psychiatric disorders, including anxiety, depression, and addiction. More recently, this endogenous opioid system has received increased attention as a potential therapeutic target for treating alcohol use disorders. In this review, we provide an overview and synthesis of preclinical studies examining the influence of alcohol (ethanol [EtOH]) exposure on DYN/KOR expression and function, as well as studies examining the effects of DYN/KOR manipulation on EtOH's rewarding and aversive properties. We then describe work that has characterized effects of KOR activation and blockade on EtOH self-administration and EtOH dependence/withdrawal-related behaviors. Finally, we address how the DYN/KOR system may contribute to stress-EtOH interactions. Despite an apparent role for the DYN/KOR system in motivational effects of EtOH, support comes from relatively few studies. Nevertheless, review of this literature reveals several common themes: (i) rodent strains genetically predisposed to consume more EtOH generally appear to have reduced DYN/KOR tone in brain reward circuitry; (ii) acute and chronic EtOH exposure typically up-regulate the DYN/KOR system; (iii) KOR antagonists reduce behavioral indices of negative affect associated with stress and chronic EtOH exposure/withdrawal; and (iv) KOR antagonists are effective in reducing EtOH consumption, but are often more efficacious under conditions that engender high levels of consumption, such as dependence or stress exposure. These results support the contention that the DYN/KOR system plays a significant role in contributing to dependence- and stress-induced elevation in EtOH consumption. Overall, more comprehensive analyses (on both behavioral and mechanistic levels) are needed to provide additional insight into how the DYN/KOR system is engaged and adapts to influence the motivation effects of EtOH. This information will be critical for the development of new pharmacological agents targeting KORs as promising novel therapeutics for alcohol use disorders and comorbid affective disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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17. Academic Difficulties in Children with Prenatal Alcohol Exposure: Presence, Profile, and Neural Correlates.
- Author
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Glass, Leila, Moore, Eileen M., Akshoomoff, Natacha, Jones, Kenneth Lyons, Riley, Edward P., and Mattson, Sarah N.
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ACADEMIC achievement evaluation ,FETAL alcohol syndrome ,ANALYSIS of covariance ,BRAIN ,CRITICAL thinking ,ORTHOGRAPHY & spelling ,MATHEMATICS ,MULTIVARIATE analysis ,NERVOUS system ,PROBABILITY theory ,READING ,STATISTICS ,DATA analysis ,REPEATED measures design ,DESCRIPTIVE statistics ,DISEASE complications - Abstract
Background Academic achievement was evaluated in children with heavy prenatal alcohol exposure to determine potential strengths and weaknesses, evaluate the utility of different definitions for identifying low academic performance, and explore the neural correlates that may underlie academic performance. Methods Children (8 to 16 years) were assessed using the WIAT- II. Patterns of performance were examined in 2 subject groups: children with heavy prenatal alcohol exposure ( n = 67) and controls ( n = 61). A repeated-measures MANCOVA examining group differences on academic domain (reading, spelling, math) scores was conducted. Post hoc comparisons examined within-group profiles. Numbers and percentage of children with low achievement were calculated using several criteria. In a subsample ( n = 42), neural correlates were analyzed using FreeSurfer v5.3 to examine relations between cortical structure (thickness and surface area) and performance. Results The alcohol-exposed group performed worse than controls on all domains and had a unique academic profile, supported by a significant group × academic domain interaction ( p < 0.001). For the alcohol-exposed group, math reasoning was significantly lower than numerical operations, which was significantly lower than spelling and word reading. Over half of the alcohol-exposed group (58.2%) demonstrated low achievement on 1 or more academic domains. The number and percentage of children meeting criteria for low achievement varied based on the domain and definition used. The imaging analysis identified several surface area clusters that were differentially related to math (L superior parietal and R lateral/middle occipital) and spelling (bilateral inferior and medial temporal) performance by group, with no relations for the other academic domains. Generally, scores improved as surface area decreased in controls, whereas no relation or a positive relation was observed in the alcohol-exposed group. Conclusions Alcohol-exposed children demonstrated deficits in academic performance across domains and definitions, with a relative weakness in math functioning. Atypical brain development may contribute to these impairments in academic achievement. Understanding academic difficulties can assist in advocating effectively for alcohol-exposed children. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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18. Negative Association Between MR-Spectroscopic Glutamate Markers and Gray Matter Volume After Alcohol Withdrawal in the Hippocampus: A Translational Study in Humans and Rats.
- Author
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Frischknecht, Ulrich, Hermann, Derik, Tunc‐Skarka, Nuran, Wang, Guo‐Ying, Sack, Markus, Eijk, Julia, Demirakca, Traute, Falfan‐Melgoza, Claudia, Krumm, Bertram, Dieter, Sandra, Spanagel, Rainer, Kiefer, Falk, Mann, Karl F., Sommer, Wolfgang H., Ende, Gabriele, and Weber‐Fahr, Wolfgang
- Subjects
ASPARTIC acid analysis ,NEURON analysis ,GLUTAMIC acid metabolism ,ALCOHOLISM ,ANIMAL experimentation ,ANTHROPOMETRY ,BRAIN ,BREATH tests ,STATISTICAL correlation ,ETHANOL ,GLUTAMIC acid ,GLUTAMINE ,HIPPOCAMPUS (Brain) ,MAGNETIC resonance imaging ,NUCLEAR magnetic resonance spectroscopy ,PROBABILITY theory ,RATS ,RESEARCH funding ,STATISTICS ,ALCOHOL withdrawal syndrome ,DATA analysis ,REPEATED measures design ,DATA analysis software ,DESCRIPTIVE statistics ,ALCOHOLIC intoxication ,ONE-way analysis of variance ,DISEASE complications - Abstract
Background Both chronic alcohol consumption and alcohol withdrawal lead to neural tissue damage which partly recovers during abstinence. This study investigated withdrawal-associated changes in glutamatergic compounds, markers of neuronal integrity, and gray matter volumes during acute alcohol withdrawal in the hippocampus, a key region in development and maintenance of alcohol dependence in humans and rats. Methods Alcohol-dependent patients ( N = 39) underwent magnetic resonance imaging ( MRI) and MR spectroscopy ( MRS) measurements within 24 hours after the last drink and after 2 weeks of abstinence. MRI and MRS data of healthy controls ( N = 34) were acquired once. Our thorough quality criteria resulted in N = 15 available spectra from the first and of N = 21 from the second measurement in patients, and of N = 19 from healthy controls. In a translational approach, chronic intermittent ethanol-exposed rats and respective controls (8/group) underwent 5 MRS measurements covering baseline, intoxication, 12 and 60 hours of withdrawal, and 3 weeks of abstinence. Results In both species, higher levels of markers of glutamatergic metabolism were associated with lower gray matter volumes in the hippocampus in early abstinence. Trends of reduced N-acetylaspartate levels during intoxication persisted in patients with severe alcohol withdrawal symptoms over 2 weeks of abstinence. We observed a higher ratio of glutamate to glutamine during alcohol withdrawal in our animal model. Conclusions Due to limited statistical power, we regard the results as preliminary and discuss them in the framework of the hypothesis of withdrawal-induced hyperglutamatergic neurotoxicity, alcohol-induced neural changes, and training-associated effects of abstinence on hippocampal tissue integrity. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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19. Associations Between Cerebellar Subregional Morphometry and Alcoholism History in Men and Women.
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Sawyer, Kayle S., Oscar‐Berman, Marlene, Mosher Ruiz, Susan, Gálvez, Daniel A., Makris, Nikos, Harris, Gordon J., and Valera, Eve M.
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ALCOHOLISM ,ANTHROPOMETRY ,CEREBELLUM ,CONFIDENCE intervals ,HAMILTON Depression Inventory ,MAGNETIC resonance imaging ,PROBABILITY theory ,RESEARCH funding ,SEX distribution ,STATISTICS ,DATA analysis ,MULTIPLE regression analysis ,DATA analysis software ,DESCRIPTIVE statistics - Abstract
Background Alcoholism has been linked to deficits in cognitive, behavioral, and emotional functions, and the cerebellum is important for optimal functioning of these abilities. However, little is known about how individual differences such as gender and drinking history might influence regional cerebellar abnormalities. Methods Volumetric analyses of the cerebellum and its subregions were performed in relation to the interaction of gender and measures of drinking history. Structural magnetic resonance imaging scans of 44 alcoholic individuals (23 men) and 39 nonalcoholic controls (18 men) were obtained. In addition to measuring total cerebellar gray and white matter volumes, we measured 64 individual cerebellar parcellation units, as well as functionally defined a priori regions of interest that have been shown to correspond to functions impaired in alcoholism. Results Total cerebellar white matter volume was smaller in alcoholic relative to nonalcoholic participants. Moreover, volumes of parcellation units varied with drinking history, showing negative associations between years of heavy drinking and the anterior lobe, the vestibulocerebellar lobe, and the spinocerebellar subdivision. The negative association between anterior volume and years of heavy drinking was driven primarily by alcoholic men. Additionally, we observed larger white and gray matter volumes for alcoholic women than for alcoholic men. Conclusions The identification of drinking-related abnormalities in cerebellar subregions lays a foundation that can be utilized to inform how cerebro-cerebellar networks are perturbed in this pathological condition. These results also provide estimates of how gender and individual differences in drinking history can predict cerebellar volumes. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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20. Interhemispheric Functional Brain Connectivity in Neonates with Prenatal Alcohol Exposure: Preliminary Findings.
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Donald, Kirsten A., Ipser, Jonathan C., Howells, Fleur M., Roos, Annerine, Fouche, Jean ‐ Paul, Riley, Edward P., Koen, Nastassja, Woods, Roger P., Biswal, Bharat, Zar, Heather J., Narr, Katherine L., and Stein, Dan J.
- Subjects
FETAL alcohol syndrome ,BRAIN ,CHI-squared test ,LONGITUDINAL method ,MAGNETIC resonance imaging ,MOTHERS ,OXYGEN ,QUESTIONNAIRES ,RESEARCH funding ,MULTIPLE regression analysis ,DATA analysis software ,DESCRIPTIVE statistics ,MANN Whitney U Test - Abstract
Background Children exposed to alcohol in utero demonstrate reduced white matter microstructural integrity. While early evidence suggests altered functional brain connectivity in the lateralization of motor networks in school-age children with prenatal alcohol exposure ( PAE), the specific effects of alcohol exposure on the establishment of intrinsic connectivity in early infancy have not been explored. Methods Sixty subjects received functional imaging at 2 to 4 weeks of age for 6 to 8 minutes during quiet natural sleep. Thirteen alcohol-exposed ( PAE) and 14 age-matched control ( CTRL) participants with usable data were included in a multivariate model of connectivity between sensorimotor intrinsic functional connectivity networks. Seed-based analyses of group differences in interhemispheric connectivity of intrinsic motor networks were also conducted. The Dubowitz neurological assessment was performed at the imaging visit. Results Alcohol exposure was associated with significant increases in connectivity between somatosensory, motor networks, brainstem/thalamic, and striatal intrinsic networks. Reductions in interhemispheric connectivity of motor and somatosensory networks did not reach significance. Conclusions Although results are preliminary, findings suggest PAE may disrupt the temporal coherence in blood oxygenation utilization in intrinsic networks underlying motor performance in newborn infants. Studies that employ longitudinal designs to investigate the effects of in utero alcohol exposure on the evolving resting-state networks will be key in establishing the distribution and timing of connectivity disturbances already described in older children. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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21. Withdrawal from Chronic Alcohol Induces a Unique CCL2 mRNA Increase in Adolescent But Not Adult Brain--Relationship to Blood Alcohol Levels and Seizures.
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Harper, Kathryn M., Knapp, Darin J., and Breese, George R.
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AGE distribution ,ANALYSIS of variance ,ANIMAL experimentation ,BRAIN ,CHI-squared test ,STATISTICAL correlation ,CYTOKINES ,ELECTROENCEPHALOGRAPHY ,ETHANOL ,FISHER exact test ,INTERLEUKINS ,LIGANDS (Biochemistry) ,POLYMERASE chain reaction ,RATS ,RESEARCH funding ,RNA ,SPASMS ,STATISTICS ,T-test (Statistics) ,TUMOR necrosis factors ,ALCOHOL withdrawal syndrome ,DATA analysis ,DATA analysis software ,DESCRIPTIVE statistics ,MANN Whitney U Test ,KRUSKAL-Wallis Test - Abstract
Background: The role of neuroimmune activation in withdrawal from chronic alcohol (ethanol) has been established in both adolescent and adult models, but direct comparisons across age are sparse. Studies need to elucidate age-dependent neuroimmune effects of alcohol and to focus research attention on age-dependent mechanisms and outcomes. Methods: Adult and adolescent rats from 2 commonly used strains, Wistar and Sprague Dawley (SD), were maintained on continuous 7%, 5.35%, 4.5%alcohol diet (CAD) or cycled 7%w/v alcohol diet for 15 days. Cortical tissue was collected at 0, 8, 16, and 24 hours postwithdrawal followed by measurement of chemokine (C-C motif) ligand 2 (CCL2), tumor necrosis factor alpha, and interleukin 1 beta mRNA with quantitative real-time polymerase chain reaction. Results: Both age groups and strains showed a strong cytokine mRNA response at 7%CAD. Further, a greater increase in CCL2 mRNA was observed in the cortex of adolescents at 7% CAD, which correlated with higher blood alcohol levels (BALs). Adolescents exposed to 5.35%CAD exhibited similar blood levels and cytokine responses as adults exposed to 7%CAD. Substantial variability in CCL2 mRNA responses was found only in adolescent rats exposed to 7%CAD. In this group, data could be segregated into high-responding and low-responding groups. Moreover, the data from the high-responding group were associated with seizures. Conclusions: Relative to other cytokine mRNAs, CCL2 exhibits a unique response profile during withdrawal from CAD. This profile is shown in adolescents, where CCL2 is uniquely influenced by the effects of seizures. Additionally, this profile is shown by the fact that only CCL2 expression correlated with BAL that transcended age groups. These data emphasize the importance of BALs and treatment regimen on developmental neuroimmune responses and suggest that select components of the neuroimmune system are more responsive to CAD withdrawal and that neurobiological mechanisms differentiating these responses should be further explored. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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22. Genetic Absence of nNOS Worsens Fetal Alcohol Effects in Mice. I: Behavioral Deficits.
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Karacay, Bahri, Bonthius, Nancy E., Plume, Jeffrey, and Bonthius, Daniel J.
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FETAL alcohol syndrome ,ANALYSIS of variance ,ANIMAL behavior ,ANIMAL experimentation ,BRAIN ,ETHANOL ,GENES ,LEARNING ,MULTIVARIATE analysis ,NITRIC oxide ,OXIDOREDUCTASES ,RATS ,RESEARCH funding ,STATISTICS ,DATA analysis ,REPEATED measures design ,DATA analysis software ,DESCRIPTIVE statistics ,GENETICS - Abstract
Background Alcohol abuse during pregnancy often induces neuropsychological problems in the offspring, including learning disorders, attention deficits, and behavior problems, all of which are prominent components of fetal alcohol spectrum disorders (FASD). However, not all children who were exposed to alcohol in utero are equally affected by it. While some children have major deficits, others are spared. This unequal vulnerability is likely due largely to differences in fetal genetics. Some fetuses appear to have certain genotypes that make them much more prone to FASD. However, to date, no gene has been identified that worsens alcohol-induced brain dysfunction. Nitric oxide (NO) is a gaseous molecule that can protect developing neurons against alcohol-induced death. In the brain, NO is produced by neuronal nitric oxide synthase ( nNOS). In this study, we examined whether homozygous mutation of the nNOS gene in mice worsens the behavioral deficits of developmental alcohol exposure. Methods Wild-type and nNOS
−/− mice received alcohol (0.0, 2.2, or 4.4 mg/g) daily over postnatal days (PDs) 4 to 9. Beginning on PD 85, the mice underwent a series of behavioral tests, including open field activity, the Morris water maze, and paired pulse inhibition. Results For the wild-type mice, alcohol impaired performance only in the water maze. In contrast, for the nNOS−/− mice, alcohol impaired performance on all 3 tasks. Furthermore, the nNOS−/− mice were substantially more impaired than wild-type mice in their performance on all 3 of the behavioral tests and at both the low (2.2) and high (4.4) doses of alcohol. Conclusions Targeted disruption of the nNOS gene worsens the behavioral impact of developmental alcohol exposure and allows alcohol-induced learning problems to emerge that are not seen in wild type. This is the first demonstration that a specific genotype can interact with alcohol to worsen functional brain deficits in an animal model of FASD. [ABSTRACT FROM AUTHOR]- Published
- 2015
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23. Brain Structural Substrates of Cognitive Procedural Learning in Alcoholic Patients Early in Abstinence.
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Ritz, Ludivine, Segobin, Shailendra, Le Berre, Anne Pascale, Lannuzel, Coralie, Boudehent, Céline, Vabret, François, Eustache, Francis, Pitel, Anne Lise, and Beaunieux, Hélène
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COMPLICATIONS of alcoholism ,ACADEMIC medical centers ,BRAIN ,COGNITION disorders ,STATISTICAL correlation ,INTERVIEWING ,LEARNING ,MATHEMATICAL statistics ,NEUROPSYCHOLOGICAL tests ,NONPARAMETRIC statistics ,REGRESSION analysis ,RESEARCH funding ,STATISTICS ,T-test (Statistics) ,DATA analysis ,PARAMETERS (Statistics) ,DATA analysis software ,DESCRIPTIVE statistics - Abstract
Background Procedural learning allows for the acquisition of new behavioral skills. Previous studies have shown that chronic alcoholism is characterized by impaired cognitive procedural learning and brain abnormalities affecting regions that are involved in the automation of new cognitive procedures in healthy individuals. The goal of the present study was to investigate the brain structural substrates of cognitive procedural learning in alcoholic patients (ALs) early in abstinence. Methods Thirty-one ALs and 31 control participants (NCs) performed the Tower of Toronto task (4 daily learning sessions, each comprising 10 trials) to assess cognitive procedural learning. We also assessed episodic and working memory, executive functions, and visuospatial abilities. ALs underwent 1.5T structural magnetic resonance imaging. Results The initial cognitive phase was longer in the AL group than in the NC group, whereas the autonomous phase was shorter. In ALs, the longer cognitive phase was predicted by poorer planning and visuospatial working memory abilities, and by smaller gray matter ( GM) volumes in the angular gyrus and caudate nucleus. ALs' planning abilities correlated with smaller GM volume in the angular gyrus. Conclusions Cognitive procedural learning was impaired in ALs, with a delayed transition from the cognitive to the autonomous phase. This slowdown in the automation of the cognitive procedure was related to lower planning abilities, which may have hampered the initial generation of the procedure to be learned. In agreement with this neuropsychological finding, a persistent relationship was found between learning performance and the GM volumes of the angular gyrus and caudate nucleus, which are usually regarded as markers of planning and initial learning of the cognitive procedure. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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24. Acute Ethanol Alters Multiple Histone Modifications at Model Gene Promoters in the Cerebral Cortex.
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Finegersh, Andrey and Homanics, Gregg E.
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ANALYSIS of variance ,ANIMAL experimentation ,BRAIN ,ETHANOL ,GENE expression ,IMMUNOLOGY technique ,MICE ,POLYMERASE chain reaction ,RESEARCH funding ,T-test (Statistics) ,WESTERN immunoblotting ,REVERSE transcriptase polymerase chain reaction ,DESCRIPTIVE statistics ,PRECIPITIN tests - Abstract
Background Ethanol (Et OH) exposure alters gene expression in the cerebral cortex ( CCx); however, mechanisms of Et OH-induced gene regulation are not well understood. We hypothesized that Et OH regulates gene expression by differentially altering histone modifications at gene promoters that are up- and down-regulated by Et OH. Such epigenetic mechanisms may ultimately contribute to Et OH-induced neuro-adaptations that underlie tolerance, dependence, and Et OH-use disorders. Methods Eight-week-old, male C57 BL/6J mice were treated with 3 g/kg Et OH (intraperitoneally) or saline and sacrificed 6 hours after injection; the CCx and hippocampus ( HC) were immediately removed and flash frozen. Chromatin immunoprecipitation was used to study the association of model gene promoters with histone modifications. Western blot was used to detect global changes in the histone modifications studied. We also used a polymerase chain reaction (PCR) array to identify changes in expression of chromatin-modifying enzymes. Results In CCx, acute Et OH decreased expression of Gad1, Hdac2, and Hdac11, which was associated with decreased histone acetylation at the Gad1 and Hdac2 promoters; we also identified increased expression of Mt1, Mt2, Egr1, which was associated with increased H3K4me3 levels at the Mt2 promoter and decreased H3K27me3 levels at the Mt1 promoter. We identified an increase in global levels of H3K4me3 in CCx as well as a global increase in H3K9ac and H3K14ac in HC. The PCR array identified decreased expression of Csrp2 bp, Hdac2, and Hdac11 as well as increased expression of Kat2b in CCx. Conclusions Acute Et OH induces chromatin remodeling at model up- and down-regulated genes in CCx. Different patterns of histone modifications at these gene promoters indicate that Et OH may be acting through multiple histone-modifying enzymes to alter gene expression; in particular, differential expression of Kat2b, Hdac2, Hdac11, and Csrp2 bp in CCx may mediate Et OH-induced chromatin remodeling. Additional studies are necessary to determine the relationship between Et OH-induced changes in histone-modifying enzymes, specific Et OH-induced histone modifications, and gene expression. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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25. Anomalous Temporoparietal Activity in Individuals with a Family History of Alcoholism: Studies from the Oklahoma Family Health Patterns Project.
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Acheson, Ashley, Franklin, Crystal, Cohoon, Andrew J., Glahn, David C., Fox, Peter T., and Lovallo, William R.
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ALCOHOLISM risk factors ,BRAIN ,COGNITION ,MAGNETIC resonance imaging ,NEUROPSYCHOLOGICAL tests ,MEMORY ,PARIETAL lobe ,RESEARCH funding ,TEMPORAL lobe ,TIME series analysis ,FAMILY history (Medicine) ,DATA analysis software ,DESCRIPTIVE statistics - Abstract
Background Individuals with a family history of alcoholism ( FH+) are at enhanced risk of developing alcohol or other substance use disorders relative to those with no family history ( FH−). Alcoholics and FH+ subjects have greater interference scores on the Stroop color-word task, suggesting these impairments may be a component of the cognitive phenotype of at-risk individuals. Methods In this study, we examined whole-brain activations in 24 FH+ and 28 FH− young adults performing the counting Stroop task, a variant of the Stroop task adapted for neuroimaging studies. Results Across all subjects, incongruent versus congruent comparisons showed activations in regions including parietal lobe areas, frontal eye fields, premotor areas, the anterior cingulate cortex, dorsolateral prefrontal cortex, and bilateral insula, indicating typical regions of activation involved in conflict resolution tasks. Compared with FH− participants, FH+ participants had greater activations in the left superior parietal lobule and precuneus ( BA 7 and 19), inferior parietal lobule ( BA 40), and middle temporal gyrus ( BA 39 and 19), indicating a predominance of greater left hemisphere activity among FH+ in temporoparietal regions. There were no regions showing greater activations in the FH− group compared with the FH+ group. Conclusions These results are consistent with less efficient cognitive functioning potentially due to poorer communication over long pathways connecting temporoparietal regions to prefrontal brain regions that participate in a distributed network involved in cognitive processing and working memory necessary for conflict resolution. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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26. Consequences of Adolescent or Adult Ethanol Exposure on Tone and Context Fear Retention: Effects of an Acute Ethanol Challenge During Conditioning.
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Broadwater, Margaret and Spear, Linda P.
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ANALYSIS of variance ,ANIMAL experimentation ,BRAIN ,ETHANOL ,FEAR ,FISHER exact test ,MEMORY ,RATS ,RESEARCH funding ,STATISTICS ,DATA analysis ,REPEATED measures design ,DESCRIPTIVE statistics ,ADOLESCENCE - Abstract
Background An acute ethanol (EtOH) challenge prior to fear conditioning typically disrupts fear retention to contextual cues to a greater degree than fear retention to a discrete tone cue, and adolescent rats are less sensitive than adults to these EtOH-induced disruptions of context fear memory. Given that some research suggests that repeated EtOH exposure during adolescence may 'lock-in' adolescent-typical EtOH sensitivity into adulthood, the purpose of this study was to determine whether adults exposed to EtOH as adolescents would be less sensitive to EtOH-induced disruptions of context fear. Methods Male Sprague-Dawley rats were given 4 g/kg intragastric EtOH (25% v/v) or water every 48 hours for a total of 11 exposures during adolescence (postnatal day [P] 28 to 48) or adulthood (P70-90). After a 22-day non-EtOH period, animals were acutely challenged with 1 g/kg intraperitoneal EtOH or saline 10 minutes prior to tone or context (noncued) fear conditioning. Tone and context fear retention was subsequently examined. Results Regardless of age or exposure history, typical deficits in context fear retention were evident after EtOH challenge during conditioning. Similarly, tone fear retention was disrupted in all animals that were trained in the presence of EtOH, which was somewhat surprising given the relative resistance of tone fear retention to an acute EtOH challenge. Conclusions These results do not support the notion of a 'lock-in' of adolescent-typical EtOH sensitivity as there was no influence of exposure age on sensitivity to the disruptive effects of an acute EtOH challenge. Thus, it appears that not all adolescent-like EtOH sensitivities persist into adulthood after prior EtOH exposure during adolescence. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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27. A Preliminary Study of the Human Brain Response to Oral Sucrose and Its Association with Recent Drinking.
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Kareken, David A., Dzemidzic, Mario, Oberlin, Brandon G., and Eiler, William J. A.
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MAGNETIC resonance imaging ,BRAIN ,ALCOHOL drinking ,OXYGEN ,QUESTIONNAIRES ,RESEARCH funding ,SUCROSE ,MULTIPLE regression analysis ,VISUAL analog scale ,DATA analysis software ,DESCRIPTIVE statistics - Abstract
Background A preference for sweet tastes has been repeatedly shown to be associated with alcohol preference in both animals and humans. In this study, we tested the extent to which recent drinking is related to blood oxygen level-dependent ( BOLD) activation from an intensely sweet solution in orbitofrontal areas known to respond to primary rewards. Methods Sixteen right-handed, non-treatment-seeking, healthy volunteers (mean age: 26 years; 75% male) were recruited from the community. All underwent a taste test using a range of sucrose concentrations, as well as functional magnetic resonance imaging ( fMRI) during pseudorandom, event-driven stimulation with water and a 0.83 M concentration of sucrose in water. Results [Sucrose > water] provoked a significant BOLD activation in primary gustatory cortex and amygdala, as well as in the right ventral striatum and in bilateral orbitofrontal cortex. Drinks/drinking day correlated significantly with the activation as extracted from the left orbital area ( r = 0.52, p = 0.04 after correcting for a bilateral comparison). Using stepwise multiple regression, the addition of rated sucrose liking accounted for significantly more variance in drinks/drinking day than did left orbital activation alone (multiple R = 0.79, p = 0.002). Conclusions Both the orbitofrontal response to an intensely sweet taste and rated liking of that taste accounted for significant variance in drinking behavior. The brain response to sweet tastes may be an important phenotype of alcoholism risk. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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28. The Effects of Alcohol on the Nonhuman Primate Brain: A Network Science Approach to Neuroimaging.
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Telesford, Qawi K., Laurienti, Paul J., Friedman, David P., Kraft, Robert A., and Daunais, James B.
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MAGNETIC resonance imaging ,ANIMAL experimentation ,BRAIN ,STATISTICAL correlation ,ETHANOL ,NEURORADIOLOGY ,PRIMATES ,RESEARCH funding ,DESCRIPTIVE statistics - Abstract
Background Animal studies have long been an important tool for basic research as they offer a degree of control often lacking in clinical studies. Of particular value is the use of nonhuman primates ( NHPs) for neuroimaging studies. Currently, studies have been published using functional magnetic resonance imaging (f MRI) to understand the default-mode network in the NHP brain. Network science provides an alternative approach to neuroimaging allowing for evaluation of whole-brain connectivity. In this study, we used network science to build NHP brain networks from f MRI data to understand the basic functional organization of the NHP brain. We also explored how the brain network is affected following an acute ethanol ( Et OH) pharmacological challenge. Methods Baseline resting-state f MRI was acquired in an adult male rhesus macaque ( n = 1) and a cohort of vervet monkeys ( n = 10). A follow-up scan was conducted in the rhesus macaque to assess network variability and to assess the effects of an acute Et OH challenge on the brain network. Results The most connected regions in the resting-state networks were similar across species and matched regions identified as the default-mode network in previous NHP f MRI studies. Under an acute Et OH challenge, the functional organization of the brain was significantly impacted. Conclusions Network science offers a great opportunity to understand the brain as a complex system and how pharmacological conditions can affect the system globally. These models are sensitive to changes in the brain and may prove to be a valuable tool in long-term studies on alcohol exposure. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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29. Binges, Brains, Birthdays, and BACs.
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Pearlson, Godfrey
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COMPLICATIONS of alcoholism ,RISK factors of neurodegeneration ,ALCOHOLS (Chemical class) ,BRAIN ,NEURORADIOLOGY ,SPECIAL days ,BINGE drinking - Abstract
The article offers information on attention-grabbing headlines such as you may be boozing your brain cells away but many of us do not accept that claim in stark, literal terms. Topics include the high oral doses of ethanol can be significantly neurotoxic is often dismissed as well rats are not people, and the extreme binge drinking is defined in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) as level III binges.
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- 2021
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30. Blockade of Ethanol-Induced Behavioral Sensitization by Sodium Butyrate: Descriptive Analysis of Gene Regulations in the Striatum.
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Legastelois, Rémi, Botia, Béatrice, and Naassila, Mickaël
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SODIUM butyrate ,ANALYSIS of variance ,ANIMAL experimentation ,BASAL ganglia ,BEHAVIOR ,BRAIN ,BUTYRIC acid ,ETHANOL ,GENE expression ,HYDROLASES ,RESEARCH methodology ,MICE ,POLYMERASE chain reaction ,RESEARCH funding ,STATISTICS ,TISSUE culture ,DATA analysis ,REPEATED measures design ,DATA analysis software ,DESCRIPTIVE statistics ,CHEMICAL inhibitors - Abstract
Background Behavioral sensitization induced by repeated ethanol ( Et OH) exposure may play a critical role in the development of alcohol dependence. Because recent data demonstrate that histone deacetylase inhibitor ( HDACi) may be of interest in the treatment of addiction, we explored the effect of the HDACi sodium butyrate ( Na B) on Et OH-induced behavioral sensitization ( EIBS) in DBA/2 J mice. We also investigated gene regulations in the striatum of sensitized mice using epigenetic- and signal transduction-related PCR arrays. Methods Mice were injected with saline or Et OH (0.5 to 2.5 g/kg) once a day for 10 days. Mice received Na B (200 to 600 mg/kg) 30 minutes before each injection (prevention protocol) or once daily between days 11 and 16 (reversal protocol). At day 17, brains were removed 30 minutes after a saline or Et OH challenge to assess gene and proteins levels. Results Only the intermediate Et OH doses (1.0 and 2.0 g/kg) were effective in inducing EIBS, and both doses were associated with specific gene regulations in the striatum. The induction of sensitization by 1.0 g/kg (but not 2.0 g/kg) Et OH was dose-dependently prevented or reversed by Na B. Among the 168 studied genes, EIBS blockade was associated with specific gene regulations ( bcl-2, bdnf, hdac4, pak1, penk, tacr1, vip...) and changes in brain-derived neurotrophic factor in both striatum and prefrontal cortex. Conclusions These results indicate that EIBS is associated with specific gene regulations in the striatum depending on the Et OH dose and that Na B can be useful in blocking some long-lasting neuro-adaptations to repeated Et OH administrations. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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31. Longitudinal Changes in White Matter Integrity Among Adolescent Substance Users.
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Bava, Sunita, Jacobus, Joanna, Thayer, Rachel E., and Tapert, Susan F.
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ALCOHOLISM ,BRAIN ,CANNABIS (Genus) ,CHILD Behavior Checklist ,INTERVIEWING ,MAGNETIC resonance imaging ,REGRESSION analysis ,RESEARCH funding ,SCALES (Weighing instruments) ,T-test (Statistics) ,DRUG abusers ,DATA analysis software ,STATE-Trait Anxiety Inventory ,DESCRIPTIVE statistics - Abstract
Background The influence of repeated substance use during adolescent neurodevelopment remains unclear as there have been few prospective investigations. The aims of this study were to identify longitudinal changes in fiber tract integrity associated with alcohol- and marijuana-use severity over the course of 1.5 years. Methods Adolescents with extensive marijuana- and alcohol-use histories by mid-adolescence ( n = 41) and youth with consistently minimal if any substance use ( n = 51) were followed over 18 months. Teens received diffusion tensor imaging and detailed substance-use assessments with toxicology screening at baseline and 18-month follow-ups (i.e., 182 scans in all), as well as interim substance-use interviews each 6 months. Results At an 18-month follow-up, substance users showed poorer white matter integrity in 7 tracts: (i) right superior longitudinal fasciculus, (ii) left superior longitudinal fasciculus, (iii) right posterior thalamic radiations, (iv) right prefrontal thalamic fibers, (v) right superior temporal gyrus white matter, (vi) right inferior longitudinal fasciculus, and (vii) left posterior corona radiata ( ps < 0.01). More alcohol use during the interscan interval predicted higher mean diffusivity (i.e., worsened integrity) in right ( p < 0.05) and left ( p = 0.06) superior longitudinal fasciculi, above and beyond baseline values in these bundles. Marijuana use during the interscan interval did not predict change over time. More externalizing behaviors at Time 1 predicted lower fractional anisotropy and higher radial diffusivity (i.e., poorer integrity) of the right prefrontal thalamic fibers ( p < 0.025). Conclusions Findings add to previous cross-sectional studies reporting white matter disadvantages in youth with substance-use histories. In particular, alcohol use during adolescent neurodevelopment may be linked to reductions in white matter quality in association fiber tracts with frontal connections. In contrast, youth who engage in a variety of risk-taking behaviors may have unique neurodevelopmental trajectories characterized by truncated development in fronto-thalamic tracts, which could have functional and clinical consequences in young adulthood. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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32. Programmed Cell Death 4 ( PDCD4): A Novel Player in Ethanol-Mediated Suppression of Protein Translation in Primary Cortical Neurons and Developing Cerebral Cortex.
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Narasimhan, Madhusudhanan, Rathinam, Marylatha, Riar, Amanjot, Patel, Dhyanesh, Mummidi, Srinivas, Yang, Hsin‐Shen, Colburn, Nancy H., Henderson, George I., and Mahimainathan, Lenin
- Subjects
ANALYSIS of variance ,ANIMAL experimentation ,APOPTOSIS ,BRAIN ,BRAIN injuries ,ENZYME inhibitors ,ETHANOL ,OXIDOREDUCTASES ,RATS ,RESEARCH funding ,STATISTICS ,T-test (Statistics) ,WESTERN immunoblotting ,DATA analysis ,DATA analysis software ,DESCRIPTIVE statistics - Abstract
Background Prenatal exposure to ethanol ( Et OH) elicits a range of neuro-developmental abnormalities, microcephaly to behavioral deficits. Impaired protein synthesis has been connected to pathogenesis of Et OH-induced brain damage and abnormal neuron development. However, mechanisms underlying these impairments of protein synthesis are not known. In this study, we illustrate the effects of Et OH on programmed cell death protein 4 ( PDCD4), a tumor and translation repressor. Methods Primary cortical neurons ( PCNs) were treated with 2.5 and 4 mg/ml Et OH for different time points (4 to 24 hours), and PDCD4 expression was detected by Western blotting. Protein synthesis was determined using [
35 S] methionine incorporation assay. Methyl cap pull-down assay was performed to establish the effect of Et OH on association of eukaryotic initiation factor 4A (eIF4A) with capped mRNA. Luciferase assay was performed to determine the in vivo translation. A 2-day acute 5-dose binge model with Et OH (4 g/kg body wt, 25% v/v) was performed in Sprague- Dawley rats at 12-hour intervals and analyzed for PDCD4, eIF4 A, and eIF4 A-methyl cap association. Results Et OH increased PDCD4 expression in a time- and dose-dependent manner in PCNs, which inhibited the association of eIF4 A with methyl cap. Et OH and ectopic PDCD4 expression suppressed in vivo translation in PCNs and RNAi targeting of PDCD4 blocked the inhibitory effect of Et OH on protein synthesis. In utero exposure of pregnant rats to Et OH resulted in a significant increase in PDCD4 in fetal cerebral cortex along with the inhibition of methyl cap-associated eIF4 A, compared with isocaloric controls. Increased PDCD4 also occurred in pooled fractions of remaining brain regions. Conclusions Our data, for the first time, illustrate that PDCD4 mediates inhibitory effects of Et OH on protein synthesis in PCNs and developing brain. [ABSTRACT FROM AUTHOR]- Published
- 2013
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33. Persistent Dose-Dependent Changes in Brain Structure in Young Adults with Low-to-Moderate Alcohol Exposure In Utero.
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Eckstrand, Kristen L., Ding, Zhaohua, Dodge, Neil C., Cowan, Ronald L., Jacobson, Joseph L., Jacobson, Sandra W., and Avison, Malcolm J.
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ANALYSIS of variance ,BRAIN ,STATISTICAL correlation ,ETHANOL ,LONGITUDINAL method ,MAGNETIC resonance imaging ,RESEARCH funding ,STATISTICS ,T-test (Statistics) ,DATA analysis ,DATA analysis software ,DESCRIPTIVE statistics ,FETUS - Abstract
Background Many children with heavy exposure to alcohol in utero display characteristic alterations in brain size and structure. However, the long-term effects of low-to-moderate alcohol exposure on these outcomes are unknown. Methods Using voxel-based morphometry and region-of-interest analyses, we examined the influence of lower doses of alcohol on gray and white matter composition in a prospectively recruited, homogeneous, well-characterized cohort of alcohol-exposed ( n = 11, age 19.5 ± 0.3 years) and control ( n = 9, age 19.6 ± 0.5 years) young adults. A large proportion of the exposed individuals were born to mothers whose alcohol consumption during pregnancy was in the low-to-moderate range. Results There were no differences in total brain volume or total gray or white matter volume between the exposed and control groups. However, gray matter volume was reduced in alcohol-exposed individuals in several areas previously reported to be affected by high levels of exposure, including the left cingulate gyrus, bilateral middle frontal gyri, right middle temporal gyrus, and right caudate nucleus. Notably, this gray matter loss was dose dependent, with higher exposure producing more substantial losses. Conclusions These results indicate that even at low doses, alcohol exposure during pregnancy impacts brain development and that these effects persist into young adulthood. [ABSTRACT FROM AUTHOR]
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- 2012
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34. A Mouse Model for Adolescent Alcohol Abuse: Stunted Growth and Effects in Brain.
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Huang, Chiming, Titus, Jennifer A., Bell, Richard L., Kapros, Tamas, Chen, Jie, and Huang, Rosa
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ANALYSIS of variance ,ANIMAL experimentation ,BODY weight ,BRAIN ,CEREBELLUM ,CEREBRAL cortex ,STATISTICAL correlation ,ETHANOL ,HUMAN growth ,MICE ,RESEARCH funding ,STATISTICS ,T-test (Statistics) ,TELENCEPHALON ,WEIGHT gain ,DATA analysis ,DATA analysis software ,DESCRIPTIVE statistics - Abstract
Background Adolescent alcohol abuse remains a serious public health concern, with nearly a third of high school seniors reporting heavy drinking in the previous month. Methods Using the high ethanol-consuming C57 BL/6 J mouse strain, we examined the effects of ethanol (3.75 g/kg, IP, daily for 45 days) on body weight and brain region mass (cerebral cortex, cerebellum, corpus callosum) during peri-adolescence (postnatal day [P]25 to 70) or adulthood ( P180 to 225) of both males and females. Results In control peri-adolescent animals, body weight gain was greater in males compared with females. In the peri-adolescent exposure group, ethanol significantly reduced body weight gain to a similar extent in both male and female mice (82 and 84% of controls, respectively). In adult animals, body weight gain was much less than that of the peri-adolescent mice, with ethanol having a small but significant effect in males but not females. Between the control peri-adolescent and adult cohorts (measurements taken at P70 and 225, respectively), there were no significant differences in the mass of the cerebral cortex or the cerebellum from either male or female mice, although the rostro-caudal length of the corpus callosum increased slightly but significantly (6.1%) between these time points. Conclusions Ethanol treatment significantly reduced the mass of the cerebral cortex in peri-adolescent (−3.1%), but not adult, treated mice. By contrast, ethanol significantly reduced the length of the corpus callosum in adult (−5.4%), but not peri-adolescent, treated mice. Future studies at the histological level may yield additional details concerning ethanol and the peri-adolescent brain. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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35. Relation Over Time Between Facial Measurements and Cognitive Outcomes in Fetal Alcohol-Exposed Children.
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Foroud, Tatiana, Wetherill, Leah, Vinci-Booher, Sophia, Moore, Elizabeth S., Ward, Richard E., Hoyme, H. Eugene, Robinson, Luther K., Rogers, Jeffrey, Meintjes, Ernesta M., Molteno, Christopher D., Jacobson, Joseph L., and Jacobson, Sandra W.
- Subjects
FETAL alcohol syndrome ,ANALYSIS of variance ,ANTHROPOMETRY ,BRAIN ,CHI-squared test ,COGNITION ,STATISTICAL correlation ,FACE ,LONGITUDINAL method ,REGRESSION analysis ,RESEARCH funding ,SCALES (Weighing instruments) ,STATISTICS ,T-test (Statistics) ,LOGISTIC regression analysis ,PILOT projects ,DATA analysis ,DATA analysis software ,DESCRIPTIVE statistics ,DISEASE complications - Abstract
Background The identification of individuals exposed prenatally to alcohol can be challenging, with only those having the characteristic pattern of facial features, central nervous system abnormality, and growth retardation receiving a clinical diagnosis of fetal alcohol syndrome ( FAS). Methods Seventeen anthropometric measurements were obtained at 5 and 9 years from 125 Cape Town, South African children, studied since birth. The children were divided into 3 groups: FAS or partial FAS ( PFAS), heavily exposed nonsyndromal ( HE), and non-alcohol-exposed controls ( C). Anthropometric measurements were evaluated for mean group differences. Logistic regression models were used to identify the subset of anthropometric measures that best predicted group membership. Anthropometric measurements were examined at the 2 ages in relation to prenatal alcohol exposure obtained prospectively from the mothers during pregnancy. Correlation of these facial measurements with key neurobehavioral outcomes including Wechsler Intelligence Scales for Children-IV IQ and eyeblink conditioning was used to assess their utility as indicators of alcohol-related central nervous system impairment. Results Significant group differences were found for the majority of the anthropometric measures, with means of these measures smaller in the FAS/ PFAS compared with HE or C. Upper facial widths, ear length, lower facial depth, and eye widths were consistent predictors distinguishing those exposed to alcohol from those who were not. Using longitudinal data, unique measures were identified that predicted facial anomalies at one age but not the other, suggesting the face changes as the individual matures. And 41% of the FAS/ PFAS group met criteria for microtia at both ages. Three of the predictive anthropometric measures were negatively related to measures of prenatal alcohol consumption, and all were positively related to at least 1 neurobehavioral outcome. Conclusions The analysis of longitudinal data identified a common set of predictors, as well as some that are unique at each age. Prenatal alcohol exposure appears to have its primary effect on brain growth, reflected by smaller forehead widths, and may suppress neural crest migration to the branchial arches, reflected by deficits in ear length and mandibular dimensions. These results may improve diagnostic resolution and enhance our understanding of the relation between the face and the neuropsychological deficits that occur. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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36. fMRI Differences Between Subjects with Low and High Responses to Alcohol During a Stop Signal Task.
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Schuckit, Marc A., Tapert, Susan, Matthews, Scott C., Paulus, Martin P., Tolentino, Neil J., Smith, Tom L., Trim, Ryan S., Hall, Shana, and Simmons, Alan
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ALCOHOLISM ,ALCOHOLISM risk factors ,ANALYSIS of covariance ,ANALYSIS of variance ,BRAIN ,BREATH tests ,CHI-squared test ,ALCOHOL drinking ,ETHANOL ,MAGNETIC resonance imaging ,MATHEMATICAL models ,MATHEMATICAL statistics ,MULTIVARIATE analysis ,QUESTIONNAIRES ,RESEARCH funding ,RISK assessment ,STATISTICAL sampling ,SELF-evaluation ,STATISTICS ,PHENOTYPES ,MULTIPLE regression analysis ,PARAMETERS (Statistics) ,TASK performance ,DATA analysis software ,DESCRIPTIVE statistics ,GENETICS - Abstract
Background: A low level of response (i.e., a low LR) to alcohol is a genetically influenced phenotype that predicts later alcoholism. While the low LR reflects, at least in part, a low brain response to alcohol, the physiological underpinnings of the low LR have only recently been addressed. Methods: Forty-nine drinking but not yet alcoholic matched pairs of 18- to 25-year-old subjects ( N = 98; 53% women) with low and high LRs as established in separate alcohol challenges were evaluated in 2 event-related functional magnetic resonance imaging (fMRI) sessions (placebo and approximately 0.7 ml/kg of alcohol) while performing a validated stop signal task. The high and low LR groups had identical blood alcohol levels during the alcohol session. Results: Significant high versus low LR group and LR group × condition effects were observed in blood oxygen level-dependent (BOLD) signal during error and inhibitory processing, despite similar LR group performance on the task. In most clusters with significant (corrected p < 0.05, clusters > 1,344 μl) LR group × alcohol/placebo condition interactions, the low LR group demonstrated relatively less, whereas the high LR group demonstrated more, error and inhibition-related activation after alcohol compared with placebo. Conclusions: This is one of the first fMRI studies to demonstrate significant differences between healthy groups with different risks of a future life-threatening disorder. The results may suggest a brain mechanism that contributes to how a low LR might enhance the risk of future heavy drinking and alcohol dependence. [ABSTRACT FROM AUTHOR]
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- 2012
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37. Positron Emission Tomography Imaging of Mu- and Delta-Opioid Receptor Binding in Alcohol-Dependent and Healthy Control Subjects.
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Weerts, Elise M., Wand, Gary S., Kuwabara, Hiroto, Munro, Cynthia A., Dannals, Robert F., Hilton, John, Frost, J. James, and McCaul, Mary E.
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PSYCHOLOGY of alcoholism ,RADIOGRAPHY ,BRAIN ,BRAIN metabolism ,NEURORADIOLOGY ,ALCOHOLISM ,ANALYSIS of covariance ,CELL receptors ,PSYCHOLOGICAL distress ,PSYCHOLOGICAL tests ,RESEARCH funding ,SCALES (Weighing instruments) ,STATISTICS ,POSITRON emission tomography ,DATA analysis ,VISUAL analog scale ,DATA analysis software ,DESCRIPTIVE statistics - Abstract
Background: The endogenous opioid system plays a significant role in alcohol dependence. The goal of the current study was to investigate regional brain mu-opioid receptor (MOR) and delta-opioid receptor (DOR) availability in recently abstinent alcohol-dependent and age-matched healthy control men and women with positron emission tomography (PET) imaging. Methods: Alcohol-dependent subjects completed an inpatient protocol, which included medically supervised withdrawal and PET imaging on day 5 of abstinence. Control subjects completed PET imaging following an overnight stay. PET scans with the MOR-selective ligand [
11 C]carfentanil (CFN) were completed in 25 alcohol-dependent and 30 control subjects. Most of these same subjects (20 alcohol-dependent subjects and 18 controls) also completed PET scans with the DOR-selective ligand [11 C]methylnaltrindole (MeNTL). Results: Volumes of interest and statistical parametric mapping analyses indicated that alcohol-dependent subjects had significantly higher [11 C]CFN binding potential (BPND ) than healthy controls in multiple brain regions including the ventral striatum when adjusting for age, gender, and smoking status. There was an inverse relationship between [11 C]CFN BPND and craving in several brain regions in alcohol-dependent subjects. Groups did not differ in [11 C]MeNTL BPND ; however, [11 C]MeNTL BPND in caudate was positively correlated with recent alcohol drinking in alcohol-dependent subjects. Conclusions: Our observation of higher [11 C]CFN BPND in alcohol-dependent subjects can result from up-regulation of MOR and/or reduction in endogenous opioid peptides following long-term alcohol consumption, dependence, and/or withdrawal. Alternatively, the higher [11 C]CFN BPND in alcohol-dependent subjects may be an etiological difference that predisposed these individuals to alcohol dependence or may have developed as a result of increased exposure to childhood adversity, stress, and other environmental factors known to increase MOR. Although the direction of group differences in [11 C]MeNTL BPND was similar in many brain regions, differences did not achieve statistical significance, perhaps as a result of our limited sample size. Additional research is needed to further clarify these relationships. The finding that alcohol-dependent subjects had higher [11 C]CFN BPND is consistent with a prominent role of the MOR in alcohol dependence. [ABSTRACT FROM AUTHOR]- Published
- 2011
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38. Diffusion Tensor Imaging of the Cerebellum and Eyeblink Conditioning in Fetal Alcohol Spectrum Disorder.
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Spottiswoode, Bruce S., Meintjes, Ernesta M., Anderson, Adam W., Molteno, Christopher D., Stanton, Mark E., Dodge, Neil C., Gore, John C., Peterson, Bradley S., Jacobson, Joseph L., and Jacobson, Sandra W.
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MAGNETIC resonance imaging ,ANALYSIS of variance ,FETAL alcohol syndrome ,BRAIN ,CEREBELLUM ,CHI-squared test ,STATISTICAL correlation ,ETHANOL ,NEUROPSYCHOLOGICAL tests ,RESEARCH funding ,SCALES (Weighing instruments) ,SUBSTANCE abuse in pregnancy ,MULTIPLE regression analysis ,CROSS-sectional method ,BLINKING (Physiology) ,DIAGNOSIS - Abstract
Background: Prenatal alcohol exposure is related to a wide range of neurocognitive effects. Eyeblink conditioning (EBC), which involves temporal pairing of a conditioned with an unconditioned stimulus, has been shown to be a potential biomarker of fetal alcohol exposure. A growing body of evidence suggests that white matter may be a specific target of alcohol teratogenesis, and the neural circuitry underlying EBC is known to involve the cerebellar peduncles. Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique that has proven useful for assessing central nervous system white matter integrity. This study used DTI to examine the degree to which the fetal alcohol-related deficit in EBC may be mediated by structural impairment in the cerebellar peduncles. Methods: Thirteen children with fetal alcohol spectrum disorder (FASD) and 12 matched controls were scanned using DTI and structural MRI sequences. The DTI data were processed using a voxelwise technique, and the structural data were used for volumetric analyses. Prenatal alcohol exposure group and EBC performance were examined in relation to brain volumes and outputs from the DTI analysis. Results: Fractional anisotropy (FA) and perpendicular diffusivity group differences between alcohol-exposed and nonexposed children were identified in the left middle cerebellar peduncle. Alcohol exposure correlated with lower FA and greater perpendicular diffusivity in this region, and these correlations remained significant even after controlling for total brain and cerebellar volumes. Conversely, trace conditioning performance was related to higher FA and lower perpendicular diffusivity in the left middle peduncle. The effect of prenatal alcohol exposure on trace conditioning was partially mediated by lower FA in this region. Conclusions: This study extends recent findings that have used DTI to reveal microstructural deficits in white matter in children with FASD. This is the first DTI study to demonstrate mediation of a fetal alcohol-related effect on neuropsychological function by deficits in white matter integrity. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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39. Adolescent Binge Drinking Linked to Abnormal Spatial Working Memory Brain Activation: Differential Gender Effects.
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Squeglia, Lindsay M., Schweinsburg, Alecia Dager, Pulido, Carmen, and Tapert, Susan F.
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BRAIN physiology ,MAGNETIC resonance imaging ,ACTIVE oxygen in the body ,ALCOHOLISM ,ANALYSIS of variance ,ATTENTION ,BRAIN ,BREATH tests ,CHILD Behavior Checklist ,COGNITION ,STATISTICAL correlation ,ETHANOL ,INTERVIEWING ,LONGITUDINAL method ,REACTION time ,RESEARCH funding ,SEX distribution ,SHORT-term memory ,SPACE perception ,STATISTICAL hypothesis testing ,T-test (Statistics) ,TASK performance ,PERCEPTUAL disorders ,BODY mass index ,CONTROL groups ,CROSS-sectional method ,DATA analysis software ,ADOLESCENCE - Abstract
Background: Binge drinking is prevalent during adolescence, and its effect on neurocognitive development is of concern. In adult and adolescent populations, heavy substance use has been associated with decrements in cognitive functioning, particularly on tasks of spatial working memory (SWM). Characterizing the gender-specific influences of heavy episodic drinking on SWM may help elucidate the early functional consequences of drinking on adolescent brain functioning. Methods: Forty binge drinkers (13 females, 27 males) and 55 controls (24 females, 31 males), aged 16 to 19 years, completed neuropsychological testing, substance use interviews, and an SWM task during functional magnetic resonance imaging. Results: Significant binge drinking status × gender interactions were found ( p < 0.05) in 8 brain regions spanning bilateral frontal, anterior cingulate, temporal, and cerebellar cortices. In all regions, female binge drinkers showed less SWM activation than female controls, while male bingers exhibited greater SWM response than male controls. For female binge drinkers, less activation was associated with poorer sustained attention and working memory performances ( p < 0.025). For male binge drinkers, greater activation was linked to better spatial performance ( p < 0.025). Conclusion: Binge drinking during adolescence is associated with gender-specific differences in frontal, temporal, and cerebellar brain activation during an SWM task, which in turn relate to cognitive performance. Activation correlates with neuropsychological performance, strengthening the argument that blood oxygen level-dependent activation is affected by alcohol use and is an important indicator of behavioral functioning. Females may be more vulnerable to the neurotoxic effects of heavy alcohol use during adolescence, while males may be more resilient to the deleterious effects of binge drinking. Future longitudinal research will examine the significance of SWM brain activation as an early neurocognitive marker of alcohol impact to the brain on future behaviors, such as driving safety, academic performance, and neuropsychological performance. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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40. Extensive Deep Gray Matter Volume Reductions in Children and Adolescents with Fetal Alcohol Spectrum Disorders.
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Nardelli, Alexa, Lebel, Catherine, Rasmussen, Carmen, Andrew, Gail, and Beaulieu, Christian
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FETAL alcohol syndrome ,AGE distribution ,ANALYSIS of variance ,BRAIN ,COGNITIVE testing ,STATISTICAL correlation ,MAGNETIC resonance imaging ,MULTIVARIATE analysis ,REGRESSION analysis ,RESEARCH funding ,STATISTICS ,STRUCTURAL frame models ,INTER-observer reliability - Abstract
Background: The link between the numerous cognitive, motor, and behavioral difficulties of individuals with fetal alcohol spectrum disorders (FASD) and underlying specific structural brain injuries can be investigated using high-resolution imaging. Differential sensitivity of the brain's 'relay' stations, namely the deep gray matter structures, may play a key factor given their multifaceted role in brain function. The purpose of our study was to analyze differences in deep gray matter volumes of children and adolescents with FASD relative to age/sex-matched controls and to examine whether any volume differences were consistent across the age range of neurodevelopment. Methods: Children and adolescents ( N = 28, 6 to 17 years) diagnosed with FASD and 56 age- and sex-matched healthy controls (i.e., 2 matched controls per FASD subject) underwent 3-dimensional T1-weighted MRI scans that were used for the automated volume measurement (FreeSurfer) of the intracranial space, total white matter, cortical gray matter, and 6 deep gray matter structures, namely the hippocampus, amygdala, thalamus, caudate, putamen, and globus pallidus, with left and right measured separately. Volumes were compared between FASD and controls, as well as changes with age. Results: Significant reductions of volume in FASD were observed for the intracranial vault (7.6%), total white matter (8.6%), total cortical gray matter (7.8%), and total deep gray matter (13.1%). All 6 deep gray matter structures showed significant volume reductions bilaterally with the caudate (approximately 16%) and globus pallidus (approximately 18%) being most affected. The hippocampus, thalamus, and globus pallidus showed reductions in all 3 age subgroups (6 to 9, 10 to 13, and 14 to 17 years) but the caudate and putamen had smaller volumes for FASD only within the 2 youngest subgroups; the amygdala was only smaller for FASD in the 2 oldest subgroups. Conclusions: Significant, but variable, volume reductions throughout the deep gray matter are observed over a wide age range of 6 to 17 years in FASD. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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41. Functional Imaging of Cognitive Control During Acute Alcohol Intoxication.
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Anderson, Beth M., Stevens, Michael C., Meda, Shashwath A., Jordan, Kathryn, Calhoun, Vince D., and Pearlson, Godfrey D.
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ANALYSIS of variance ,BEHAVIOR ,BRAIN ,ALCOHOL drinking ,ETHANOL ,HEMODYNAMICS ,MAGNETIC resonance imaging ,REACTION time ,RESEARCH funding ,T-test (Statistics) ,REPEATED measures design - Abstract
The anterior cingulate and several other prefrontal and parietal brain regions are implicated in error processing and cognitive control. The effects of different doses of alcohol on activity within these brain regions during a functional magnetic resonance imaging (fMRI) task where errors are frequently committed have not been fully explored. This study examined the impact of a placebo [breath alcohol concentration (BrAC) = 0.00%], moderate (BrAC = 0.05%), and high (BrAC = 0.10%) doses of alcohol on brain hemodynamic activity during a functional MRI (fMRI) Go/No-Go task in 38 healthy volunteers. Alcohol increased reaction time and false alarm errors in a dose-dependent manner. fMRI analyses showed alcohol decreased activity in anterior cingulate, lateral prefrontal cortex, insula, and parietal lobe regions during false alarm responses to No-Go stimuli. These findings indicate that brain regions implicated in error processing are affected by alcohol and might provide a neural basis for alcohol's effects on behavioral performance. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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42. Commentary: Linking Cortical and Subcortical Developmental Trajectories to Behavioral Deficits in a Mouse Model of Prenatal Alcohol Exposure.
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Weinberg, Joanne
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FETAL alcohol syndrome ,ANTHROPOMETRY ,BIOLOGICAL models ,BRAIN ,NEUROANATOMY - Abstract
The author criticizes the article by C. W. Abbott and colleagues titled "The Impact of Prenatal Ethanol Exposure on Neuroanatomical and Behavioral Development" which focuses on the impact of abnormal gene expression on learning disabilities and behavior. Topics discussed include the lower birthweights of prenatal ethanol exposure (PrEE) mice reported by the team, the alteration of the development of sensory areas by the PrEE, and the relation between the behavior and the brain.
- Published
- 2016
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43. Microstructural Corpus Callosum Anomalies in Children With Prenatal Alcohol Exposure: An Extension of Previous Diffusion Tensor Imaging Findings.
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Wozniak, Jeffrey R., Muetzel, Ryan L., Mueller, Bryon A., McGee, Christie L., Freerks, Melesa A., Ward, Erin E., Nelson, Miranda L., Chang, Pi-Nian, and Lim, Kelvin O.
- Subjects
CORPUS callosum ,HUMAN abnormalities ,ALCOHOLISM in pregnancy ,COMPLICATIONS of alcoholism ,THERMAL diffusivity ,DIFFUSION tensor imaging ,FETAL alcohol syndrome - Abstract
Background: Several studies have now shown corpus callosum abnormalities using diffusion tensor imaging (DTI) in children with fetal alcohol spectrum disorders (FASD) in comparison with nonexposed controls. The data suggest that posterior regions of the callosum may be disproportionately affected. The current study builds on previous efforts, including our own work, and moves beyond midline corpus callosum to probe major inter-hemispheric white matter pathways with an improved DTI tractographic method. This study also expands on our prior work by evaluating a larger sample and by incorporating children with a broader range of clinical effects including full-criteria fetal alcohol syndrome (FAS). Methods: Participants included 33 children with FASD (8 FAS, 23 partial FAS, 2 static encephalopathy) and 19 nonexposed controls between the ages of 10 and 17 years. Participants underwent DTI scans and intelligence testing. Groups (FASD vs. controls) were compared on fractional anisotropy (FA) and mean diffusivity (MD) in 6 white matter tracts projected through the corpus callosum. Exploratory analyses were also conducted examining the relationships between DTI measures in the corpus callosum and measures of intellectual functioning and facial dysmorphology. Results: In comparison with the control group, the FASD group had significantly lower FA in 3 posterior tracts of the corpus callosum: the posterior mid-body, the isthmus, and the splenium. A trend-level finding also suggested lower FA in the genu. Measures of white matter integrity and cognition were correlated and suggest some regional specificity, in that only posterior regions of the corpus callosum were associated with visual-perceptual skills. Correlations between measures of facial dysmorphology and posterior regions of the corpus callosum were nonsignificant. Conclusions: Consistent with previous DTI studies, these results suggest that microstructural posterior corpus callosum abnormalities are present in children with prenatal alcohol exposure and cognitive impairment. These abnormalities are clinically relevant because they are associated with cognitive deficits and appear to provide evidence of abnormalities associated with prenatal alcohol exposure independent of dysmorphic features. As such, they may yield important diagnostic and prognostic information not provided by the traditional facial characteristics. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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44. Alcohol in Moderation, Cardioprotection, and Neuroprotection: Epidemiological Considerations and Mechanistic Studies.
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Collins, Michael A., Neafsey, Edward J., Mukamal, Kenneth J., Gray, Mary O., Parks, Dale A., Das, Dipak K., and Korthuis, Ronald J.
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CARDIOTONIC agents ,NEUROPROTECTIVE agents ,ALCOHOL ,ALCOHOL drinking ,ADENOSINES ,CEREBROVASCULAR disease ,DEMENTIA ,ENDOTOXINS ,AMYLOID - Abstract
In contrast to many years of important research and clinical attention to the pathological effects of alcohol (ethanol) abuse, the past several decades have seen the publication of a number of peer-reviewed studies indicating the beneficial effects of light-moderate, nonbinge consumption of varied alcoholic beverages, as well as experimental demonstrations that moderate alcohol exposure can initiate typically cytoprotective mechanisms. A considerable body of epidemiology associates moderate alcohol consumption with significantly reduced risks of coronary heart disease and, albeit currently a less robust relationship, cerebrovascular (ischemic) stroke. Experimental studies with experimental rodent models and cultures (cardiac myocytes, endothelial cells) indicate that moderate alcohol exposure can promote anti-inflammatory processes involving adenosine receptors, protein kinase C (PKC), nitric oxide synthase, heat shock proteins, and others which could underlie cardioprotection. Also, brain functional comparisons between older moderate alcohol consumers and nondrinkers have received more recent epidemiological study. In over half of nearly 45 reports since the early 1990s, significantly reduced risks of cognitive loss or dementia in moderate, nonbinge consumers of alcohol (wine, beer, liquor) have been observed, whereas increased risk has been seen only in a few studies. Physiological explanations for the apparent CNS benefits of moderate consumption have invoked alcohol’s cardiovascular and/or hematological effects, but there is also experimental evidence that moderate alcohol levels can exert direct “neuroprotective” actions—pertinent are several studies in vivo and rat brain organotypic cultures, in which antecedent or preconditioning exposure to moderate alcohol neuroprotects against ischemia, endotoxin, β-amyloid, a toxic protein intimately associated with Alzheimer’s, or gp120, the neuroinflammatory HIV-1 envelope protein. The alcohol-dependent neuroprotected state appears linked to activation of signal transduction processes potentially involving reactive oxygen species, several key protein kinases, and increased heat shock proteins. Thus to a certain extent, moderate alcohol exposure appears to trigger analogous mild stress-associated, anti-inflammatory mechanisms in the heart, vasculature, and brain that tend to promote cellular survival pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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45. Many Infants Prenatally Exposed to High Levels of Alcohol Show One Particular Anomaly of the Corpus Callosum.
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Bookstein, Fred L., Connor, Paul D., Huggins, Janet E., Barr, Helen M., Pimentel, Kristi D., and Streissguth, Ann P.
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TOXICOLOGY of alcohol ,FETAL alcohol syndrome ,PERINATAL pharmacology ,PHYSIOLOGICAL effects of alcohol ,INFANTS ,PEDIATRIC pharmacology ,INFANT physiology ,CORPUS callosum ,TELENCEPHALON ,BRAIN - Abstract
Introduction: Effects of prenatal alcohol exposure on the brain are seen at every age. The earlier they can be quantified, the better the prognosis for the affected child. Here we show measurable alcohol effects at birth on a structure currently used for nosology only much later in life. Methods: Midline shape of the corpus callosum was imaged in infants via averaged unwarped transfontanelle ultrasound. We compared measures of these shapes among 23 infants prenatally exposed to high levels of alcohol and 21 infants unexposed to alcohol or only lightly exposed. Results: A particular feature of the corpus callosum, the appearance of a “hook” (obtuse angle) between the splenium and the long diameter of the arch in this plane, is strongly associated with prenatal alcohol exposure. In half of the high-exposed infants, the splenium angle is larger than in any of the unexposed brains. Simply characterizing this angle as less than or greater than 90° detects 12 of the 23 exposed infants as anomalous with only 1 false positive among the unexposed. This apparently direct effect of prenatal ethanol exposure on the details of the callosum in about half the at-risk subjects cannot be attributed to any of several plausible competing exposures or other confounding factors applying during or after gestation. Conclusion: An average of the images for the unexposed subjects has the geometry of textbook images of normal babies; but the average for the subgroup of high-angle subjects may serve as a template or guide to this regional damage parallel to the familiar photographic exemplars that help to assess facial signs. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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46. Reinforcing Effects of Central Ethanol Injections in Newborn Rat Pups.
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Nizhnikov, Michael E., Varlinskaya, Elena I., and Spear, Norman E.
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ALCOHOL ,NEWBORN infants ,RATS ,MURIDAE ,ALCOHOLISM ,DRUG administration ,LEMON ,OLFACTORY cortex ,BRAIN - Abstract
Background: Newborn rat pups readily ingest ethanol of low to moderate concentrations and are sensitive to its reinforcing effects. Given that early ethanol exposure can promote its future abuse, it is vital to discover the mechanisms behind reinforcing effects of ethanol at this stage of life. Methods: Cesarean-delivered 3- to 4-hour-old rat pups were exposed to lemon odor (unconditioned stimulus) either paired or explicitly unpaired with central injections of saline or ethanol (25, 50, 100, 200, or 400 mg%) in a volume of 1 μL. One hour following conditioning subjects were tested on a surrogate nipple providing water in the presence of lemon odor. Reinforcement from ethanol's central effects was indexed by significantly greater attachment time on a lemon-scented nipple in paired subjects than in unpaired or saline controls. Results: Rats centrally injected with 25 to 200 mg% ethanol in the presence of lemon odor spent significantly more time attached to a lemon-scented surrogate nipple providing water than did their saline-injected or unpaired counterparts. Those injected with 400 mg% ethanol did not differ from their corresponding controls. No detectable brain alcohol content was found in the assay of whole brain for ethanol levels. Conclusions: These results indicate that 3- to 4-hour-old rat pups find central injections of 25 to 200 mg% ethanol reinforcing. This procedure virtually eliminates ethanol's chemosensory or caloric attributes as the source of ethanol reinforcement. The present classical olfactory conditioning paradigm can be used to further study mechanisms of this apparently pharmacological reinforcement by ethanol in newborn rat pups. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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47. Longitudinal Brain Magnetic Resonance Imaging Study of the Alcohol-Preferring Rat. Part I: Adult Brain Growth.
- Author
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Sullivan, Edith V., Adalsteinsson, Elfar, Sood, Rohit, Mayer, Dirk, Bell, Richard, McBride, William, Ting-Kai Li, and Pfefferbaum, Adolf
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BRAIN ,RATS ,MAGNETIC resonance imaging ,MORPHOLOGY ,ALCOHOL ,AGE ,ALCOHOLISM ,AUTOPSY ,NUTRITION ,EXERCISE ,AGING - Abstract
Background: The alcohol-preferring (P) rat, a Wistar strain selectively bred to consume large amounts of alcohol voluntarily, has been used as an animal model of human alcoholism for 3 decades. Heretofore, knowledge about brain morphology has been confined to postmortem examination. Quantitative neuroimaging procedures make it feasible to examine the potential longitudinal effects of alcohol exposure in vivo, while controlling modifying factors, such as age, nutrition, and exercise. To date, few imaging studies have considered what morphological changes occur with age in the rodent brain, and none has systematically applied quantitative neuroimaging approaches to measure volume changes in regional brain structures over extended periods in the adult rat. Methods: We used structural magnetic resonance imaging (MRI) in a longitudinal design to examine 2 cohorts of adult P rats, never exposed to alcohol: Cohort A included 8 rats, 7 of which survived the entire study (578 days) and 4 MRI sessions; Cohort B included 9 rats, all of which survived the study (452 days) and 5 MRI sessions. Results: Growth in whole-brain volume reached maximal levels by about 450 days of age, whereas body weight continued its gain without asymptote. Growth was not uniform across the brain structures measured. Over the initial 12 months of the study, the corpus callosum area expanded 36%, cerebellum 17%, and hippocampus 10%, whereas ventricle size was unchanged. Factors affecting growth rate estimates included litter effects, MR image signal-to-noise ratio, and measurement error. Conclusion: Unlike longitudinal human reports of regional volume declines in aging brain tissue, several brain structures in adult rats continued growing, and some growth patterns were litter-dependent. Determining normal regional growth patterns of brain and of the substantial variance exerted by litter differences, even in selectively bred rats, is essential for establishing baselines against which normal and aberrant dynamic changes can be detected in animal models of aging and disease. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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48. Analysis of Metallothionein Brain Gene Expression in Relation to Ethanol Preference in Mice Using Cosegregation and Gene Knockouts.
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Loney, Kimberly D., Uddin, Raihan K., and Singh, Shiva M.
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METALLOTHIONEIN ,BRAIN ,GENE expression ,ALCOHOL ,MICE ,HORMONES ,OXIDIZING agents ,GENES ,MESSENGER RNA ,POLYMERASE chain reaction ,WEIGHT gain ,OBESITY - Abstract
Background: Metallothioneins (MTs) are ubiquitously expressed intracellular proteins that bind heavy metals and are involved in cytoprotection against several types of stress agents including chemicals, hormones, and oxidants. We have previously reported 1 isoform, MT-II, as a possible candidate gene for ethanol (EtOH) preference (EP) determination in mice. Methods: Semiquantitative RT-PCR was used to determine brain mRNA levels of MT-I and MT-III in 4 inbred mouse strains with variable EP. Following this, cosegregation of MT-II brain expression with EP was analyzed in F2 mice from 2 intercrosses (C57BL/6J × BALB/cJ and C57BL/6J × DBA/2J). Studies on MT-I/MT-II knockout (KO) mice were also undertaken to further explore this relationship. Results: Our results suggest that MT-I is responsive to EtOH, with no evidence of basal-level differences between strains. Conversely, MT-III shows no EtOH response, yet indicates a possible strain-specific feature with C57BL/6J having the lowest levels of brain MT-III. Metallothionein-II expression cosegregates with EP in F2 mice from a C57BL/6J (preferring) and DBA/2J (avoiding) intercross. Although F2 mice from a cross with C57BL/6J and BALB/cJ (avoiding) strains follow a similar pattern, the results are not statistically significant. Metallothionein-I/MT-II knockout (MT-KO) mice appear to have smaller litter sizes as well as higher weight compared with controls (129S1/SvImJ) and also show a slight increase in EP. Conclusions: Metallothionein-II remains the primary candidate of the mouse MT gene family for involvement in EP. Its effect on EP appears to be dependent on the genetic background. Such conclusions are based on results from C57BL/6J, BALB/cJ, DBA/2J, and 129 inbred mouse strains. Evidence also points to shared neural pathways involved in weight gain and obesity. The complex interactions between MT-II, EP, and weight gain/obesity remain to be studied. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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49. Detection and Localization of Protein-Acetaldehyde Adducts in Rat Brain After Chronic Ethanol Treatment.
- Author
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Upadhya, Sudarshan C. and Ravindranath, Vijayalakshmi
- Abstract
Background: Ethanol is metabolized to acetaldehyde in the cell, which is potentially deleterious because it can react with cellular proteins and form protein-acetaldehyde adducts, which can interfere with normal cellular function. Because the primary site of ethanol action is the brain, the present study was carried out to determine whether protein-acetaldehyde adducts are formed in rat brain after chronic ethanol administration. Methods: Rats were treated with ethanol for 1 year, and the formation of protein-acetaldehyde adducts was examined by immunoblot analysis and localized in brain by immunohistochemical analysis by using affinity purified antibody to acetaldehyde-hemocyanin adduct. Results: In the brain of rats administered ethanol for up to 1 year, protein-acetaldehyde adducts were detectable by immunoblot analysis. In brain, mitochondria was the primary site of adduct formation, unlike the liver, where the major protein-acetaldehyde adduct has been detected in the cytosol. Immunohistochemical localization of protein-acetaldehyde adducts in chronic ethanol-treated rat brain demonstrated the selective presence of adducts in cortical neurons, granule cell layer of dentate gyrus, neurons in the midbrain, and granular cell layers of cerebellum. Conclusions: These results demonstrate the significant formation of protein-acetaldehyde adducts in rat brain after ethanol ingestion. The modification of mitochondrial proteins in brain by protein-acetaldehyde adduct formation is significant because mitochondrial dysfunction has been implicated in neurodegeneration. [ABSTRACT FROM AUTHOR]
- Published
- 2002
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50. Ethanol Consumption Alters Electroretinograms and Depletes Neural Tissues of Docosahexaenoic Acid in Rhesus Monkeys: Nutritional Consequences of a Low n-3 Fatty Acid Diet.
- Author
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Pawlosky, Robert J., Bacher, John, and Salem, Norman
- Abstract
Background: Alcohol amblyopia is a rare neuropathy characterized by the development of blurred vision and a reduction in visual acuity. Further diagnostic details of this condition have shown abnormalities in the electroretinogram (ERG) that include an increase in implicit times in the a- and b-waves and a depression of b-wave amplitude. Methods: Periodically, the ERGs and the fatty acyl composition of nervous tissue were analyzed from alcohol-consuming rhesus monkeys ( Macaca mulatta) (mean consumption 2.6 g kg/day over a 5-year period) and controls that were maintained on a nutritionally sufficient diet that had low, yet adequate, amounts of linoleic acid but very low α-linolenic acid. Results: Animals consuming alcohol had increased a- and b-wave implicit times and decreased b-wave amplitudes in their electroretinograms compared with those of the dietary control group at 2.5 and 5 years. The fatty acyl composition of brain specimens obtained by surgical biopsy at baseline, 2.5 years, and 5 years demonstrated that docosahexaenoic acid (DHA) had decreased in both groups of animals compared with baseline values. In the brains of the alcohol-treated animals, DHA was even further decreased (2.5 years: −20%; 5 years: −33%) compared with the diet controls. In the retinas of the alcohol-consuming animals at 5 years, there was a similar decrease in DHA (-35%) compared with controls. Generally, the n-6 fatty acid, docosapentaenoic acid (DPAn-6) increased in these tissues, apparently compensating for the loss of DHA. Conclusions: A reciprocal change in the DHA/DPAn-6 ratio is known to be associated with abnormal electroretinograms in a number of species. Thus, a marginal intake of n-3 fatty acids in some alcohol abusers may, in part, be responsible for the biochemical changes that underlie the diminished retinal function associated with the visual abnormalities observed in alcohol-amblyopic patients. [ABSTRACT FROM AUTHOR]
- Published
- 2001
- Full Text
- View/download PDF
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