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Dominic T. Cheng,
Ernesta M. Meintjes,
Mark E. Stanton,
John E. Desmond,
Mariska Pienaar, Neil C. Dodge,
John M. Power,
Christopher D. Molteno,
John F. Disterhoft,
Joseph L. Jacobson,
Sandra W. Jacobson
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ABSTRACT: This study characterized human cerebellar activity during eyeblink classical conditioning (EBC)
in children and adults using functional magnetic resonance imaging (fMRI). During fMRI, participants
were administered delay conditioning trials, in which the conditioned stimulus (a tone) precedes, overlaps,
and coterminates with the unconditioned stimulus (a corneal airpuff). Behavioral eyeblink responses and
brain activation were measured concurrently during two phases: pseudoconditioning, involving presentations
of tone alone and airpuff alone, and conditioning, during which the tone and airpuff were paired.
Although all participants demonstrated significant conditioning, the adults produced more conditioned
responses (CRs) than the children. When brain activations during pseudoconditioning were subtracted
from those elicited during conditioning, significant activity was distributed throughout the cerebellar cortex
(Crus I-II, lateral lobules IV-IX, and vermis IV–VI) in all participants, suggesting multiple sites of associative
learning-related plasticity. Despite their less optimal behavioral performance, the children showed
greater responding in the pons, lateral lobules VIII, IX, and Crus I, and vermis VI, suggesting that they may
require greater activation and/or the recruitment of supplementary structures to achieve successful conditioning.
Correlation analyses relating brain activations to behavioral CRs showed a positive association of
activity in cerebellar deep nuclei (including dentate, fastigial, and interposed nuclei) and vermis VI with
CRs in the children. This is the first study to compare cerebellar cortical and deep nuclei activations in children
versus adults during EBC.
Human Brain Mapping 01/2013; · 5.88 Impact Factor
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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.
Alcoholism Clinical and Experimental Research 05/2012; · 3.34 Impact Factor
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ABSTRACT: Although children with heavy prenatal alcohol exposure may exhibit the distinctive facial dysmorphology seen in full or partial fetal alcohol syndrome (FAS/PFAS), many lack that dysmorphology. This study examined the functional organization of working memory in the brain in three groups of children-those meeting diagnostic criteria for FAS or PFAS, heavily exposed (HE) nonsyndromal children, and healthy controls. A verbal n-back task (1-back and 0-back) was administered to 47 children (17 with FAS/PFAS, 13 HE, and 17 controls) during fMRI. Intra-group one-sample t-tests were used to identify activity regions of interest central to verbal working memory including the dorsal prefrontal cortex (dPFC), inferior frontal gyrus, caudate/putamen, parietal cortex, and cerebellar Crus I/lobule VI and lobule VIIB-IX. Whereas groups did not differ in task sensitivity, fMRI analyses suggested different patterns of sub-network recruitment across groups. Controls primarily recruited left inferior frontal gyrus (Broca's area). By contrast, HE primarily recruited an extensive set of fronto-striatal regions, including left dPFC and left caudate, and the FAS/PFAS group relied primarily on two cerebellar subregions and parietal cortex. This study is, to our knowledge, the first to demonstrate differential recruitment of critical brain regions that subserve basic function in children with different fetal alcohol spectrum disorders compared to controls. The distinct activation patterns seen in the two exposed groups may be related to substantial differences in alcohol dose/occasion to which these groups were exposed in utero. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
Human Brain Mapping 03/2012; · 5.88 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Alcoholism Clinical and Experimental Research 07/2011; 35(12):2174-83. · 3.34 Impact Factor
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ABSTRACT: Poor arithmetic performance is among the most sensitive outcomes associated with prenatal alcohol exposure and is also common in individuals with attention-deficit hyperactivity disorder (ADHD). We hypothesized that prenatal alcohol exposure would be associated with deficits in the most fundamental aspects of number processing, representation of quantity and distance, whereas ADHD would be associated with deficits in calculation, the form of number processing most dependent on attention and memory.
Two hundred and sixty-two inner-city, African American adolescents, who had been evaluated prospectively for prenatal alcohol exposure and ADHD, were assessed on a number-processing test comprised of 7 subtests.
More heavily alcohol-exposed adolescents were 4 times more likely to meet diagnostic criteria for ADHD than those whose mothers abstained from alcohol use during pregnancy. Two dimensions of number processing were identified in a factor analysis-magnitude comparison and calculation. As hypothesized, prenatal alcohol exposure was more strongly related to the former and ADHD to the latter. Moreover, the relation of prenatal alcohol to calculation was fully mediated by magnitude comparison, whereas the relation of ADHD to calculation was mediated by IQ but not by magnitude comparison.
These data confirm findings from previous studies identifying arithmetic as a particularly sensitive developmental endpoint for prenatal alcohol exposure. Whereas difficulties with arithmetic in ADHD are mediated by domain-general deficits in overall cognitive ability, fetal alcohol-related arithmetic difficulties are mediated primarily by a specific deficit in the core quantity system involving the ability to mentally represent and manipulate number. These data suggest that different interventions are likely to be effective for remediating arithmetic problems in children with prenatal alcohol exposure than in non-exposed children with ADHD.
Alcoholism Clinical and Experimental Research 12/2010; 35(3):431-42. · 3.34 Impact Factor
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Sandra W Jacobson,
Mark E Stanton, Neil C Dodge,
Mariska Pienaar,
Douglas S Fuller,
Christopher D Molteno,
Ernesta M Meintjes,
H Eugene Hoyme,
Luther K Robinson,
Nathaniel Khaole,
Joseph L Jacobson
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ABSTRACT: Classical eyeblink conditioning (EBC) involves contingent temporal pairing of a conditioned stimulus (e.g., tone) with an unconditioned stimulus (e.g., air puff). Impairment of EBC has been demonstrated in studies of alcohol-exposed animals and in children exposed prenatally at heavy levels.
Fetal alcohol syndrome (FAS) was diagnosed by expert dysmorphologists in a large sample of Cape Coloured, South African children. Delay EBC was examined in a new sample of 63 children at 11.3 years, and trace conditioning in 32 of the same children at 12.8 years. At each age, 2 sessions of 50 trials each were administered on the same day; 2 more sessions the next day, for children not meeting criterion for conditioning.
Six of 34 (17.6%) children born to heavy drinkers were diagnosed with FAS, 28 were heavily exposed nonsyndromal (HE), and 29 were nonexposed controls. Only 33.3% with FAS and 42.9% of HE met criterion for delay conditioning, compared with 79.3% of controls. The more difficult trace conditioning task was also highly sensitive to fetal alcohol exposure. Only 16.7% of the FAS and 21.4% of HE met criterion for trace conditioning, compared with 66.7% of controls. The magnitude of the effect of diagnostic group on trace conditioning was not greater than the effect on short delay conditioning, findings consistent with recent rat studies. Longer latency to onset and peak eyeblink CR in exposed children indicated poor timing and failure to blink in anticipation of the puff. Extended training resulted in some but not all of the children reaching criterion.
These data showing alcohol-related delay and trace conditioning deficits extend our earlier findings of impaired EBC in 5-year-olds to school-age. Alcohol-related impairment in the cerebellar circuitry required for both forms of conditioning may be sufficient to account for the deficit in both tasks. Extended training was beneficial for some exposed children. EBC provides a well-characterized model system for assessment of degree of cerebellar-related learning and memory dysfunction in fetal alcohol exposed children.
Alcoholism Clinical and Experimental Research 11/2010; 35(2):250-64. · 3.34 Impact Factor
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ABSTRACT: This study examined effects of iron deficiency anemia (IDA) on specific domains of infant cognitive function and the role of IDA-related socioemotional deficits in mediating and/or moderating these effects.
Infants were recruited during routine 9-month visits to an inner-city clinic. IDA was defined as hemoglobin level <110 g/L with > or =2 abnormal iron deficiency indicators (mean corpuscular volume, red cell distribution width, zinc protoporphyrin, transferrin saturation, and ferritin). At 9 and 12 months, the Fagan Test of Infant Intelligence (FTII); A-not-B task; Emotionality, Activity, and Sociability Temperament Survey; and Behavior Rating Scale were administered. Analyses were adjusted for potential confounders, including age and sociodemographic variables.
Twenty-eight infants met criteria for IDA, 28 had nonanemic iron deficiency (NA ID) and 21 had iron sufficiency (IS). There was a linear effect for object permanence at 9 months: infants with IDA were least likely to exhibit object permanence, IS most likely, and NA ID intermediate. Infants with IDA and those with hemoglobin level < or =105 g/L showed poorer recognition memory on the FTII than infants without IDA. The Behavior Rating Scale orientation/engagement measure partially mediated these effects. Stronger effects of IDA on these outcomes were seen in infants who scored more poorly on the socioemotional measures.
These data indicate poorer object permanence and short-term memory encoding and/or retrieval in infants with IDA at 9 months. These cognitive effects were attributable, in part, to IDA-related deficits in socioemotional function. Children with poor socioemotional performance seem to be more vulnerable to the effects of IDA on cognitive function.
PEDIATRICS 08/2010; 126(2):e427-34. · 4.47 Impact Factor
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ABSTRACT: The attention and cognitive problems seen in individuals with a history of prenatal alcohol exposure often resemble those associated with attention deficit hyperactivity disorder (ADHD), but few studies have directly assessed the unique influence of each on neurobehavioral outcomes.
We recorded event-related potentials (ERPs) during a Go/No-go response inhibition task in young adults with prospectively obtained histories of prenatal alcohol exposure and childhood ADHD.
Regardless of prenatal alcohol exposure, participants with childhood ADHD were less accurate at inhibiting responses. However, only the ADHD group without prenatal alcohol exposure showed a markedly diminished P3 difference between No-go and Go, which may reflect a more effortful strategy related to inhibitory control at the neural processing level.
This finding supports a growing body of evidence suggesting that the manifestation of idiopathic ADHD symptoms may stem from a neurophysiologic process that is different from the ADHD symptomatology associated with prenatal alcohol exposure. Individuals who have been prenatally exposed to alcohol and present with ADHD symptomatology may represent a unique endophenotype of the disorder, which may require different treatment approaches from those found to be effective with idiopathic ADHD.
Alcoholism Clinical and Experimental Research 04/2010; 34(4):617-27. · 3.34 Impact Factor
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Neil C Dodge,
Joseph L Jacobson,
Christopher D Molteno,
Ernesta M Meintjes,
Sumana Bangalore,
Vaibhav Diwadkar,
Eugene H Hoyme,
Luther K Robinson,
Nathaniel Khaole,
Malcolm J Avison,
Sandra W Jacobson
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ABSTRACT: Previous research has demonstrated that heavy prenatal alcohol exposure affects the size and shape of the corpus callosum (CC) and compromises interhemispheric transfer of information. The aim of this study was to confirm the previous reports of poorer performance on a finger localization test (FLT) of interhemispheric transfer in a cohort of heavily exposed children and to extend these findings to a cohort of moderately exposed young adults.
In Study 1, the FLT was administered to 40 heavily exposed and 23 nonexposed children from the Cape Coloured community of Cape Town, South Africa, who were evaluated for fetal alcohol syndrome (FAS) dysmorphology and growth. Anatomical images of the CC were obtained using structural MRI on a subset of these children. In Study 2, the FLT was administered to a cohort of 85 moderate-to-heavily exposed young adults participating in a 19-year follow-up assessment of the Detroit Prenatal Alcohol Exposure cohort, whose alcohol exposure had been ascertained prospectively during gestation.
In Study 1, children with FAS showed more transfer-related errors than controls after adjustment for confounding, and increased transfer-related errors were associated with volume reductions in the isthmus and splenium of the CC. In Study 2, transfer-related errors were associated with quantity of alcohol consumed per occasion during pregnancy. More errors were made if the mother reported binge drinking (> or =5 standard drinks) during pregnancy than if she drank regularly (M > or = 1 drink/day) without binge drinking.
These findings confirm a previous report of impaired interhemispheric transfer of tactile information in children heavily exposed to alcohol in utero and extend these findings to show that these deficits are also seen in more moderately exposed individuals, particularly those exposed to binge-like pregnancy drinking.
Alcoholism Clinical and Experimental Research 06/2009; 33(9):1628-37. · 3.34 Impact Factor
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ABSTRACT: Neuropeptide S (NPS) is a 20-amino-acid peptide, identified in the brain and periphery, that is reported to regulate arousal, anxiety, and feeding behavior. Studies were conducted to determine whether this peptide would alter ethanol intake, sucrose intake, anxiety, and general motor activity in alcohol-preferring (P) and -nonpreferring (NP) rats.
Experiment 1: P and NP rats were given 8 weeks of continuous access to ethanol (15% w/v) and water. All rats were implanted with a cannula aimed at either the left or right lateral ventricle and 1 week later were infused with NPS (0.075, 0.3, 1.2 nmol) or artificial cerebrospinal fluid (aCSF) and tested for ethanol, food, and water intake. Experiment 2: The same doses of NPS were administered to a group of P rats and intake of 2.5% (w/v) sucrose was measured. Experiment 3: Infusions of NPS (1.2 nmol) or aCSF were administered to P rats prior to a 5-minute test on an elevated plus maze. Experiment 4: Ethanol naive P and NP rats were infused with NPS (0.075, 0.15, 0.3, 0.6, and 1.2 nmol) or aCSF prior to a 20-minute test in activity monitors.
NPS reduced ethanol intake in P, but not in NP rats. It did not influence sucrose solution intake in P rats. However, an increase in food intake was seen in both rat lines following lower doses of the peptide. NPS did neither alter anxiety-like behavior in the elevated plus maze test nor was there an effect on general motor activity; however, there was an increase in the amount of time spent in the center of the activity monitors following infusions of 0.6 nmol of NPS in P, but not in NP rats, indicating anxioltyic actions of the peptide.
These data suggest a role for NPS in the modulation of ethanol drinking and possibly anxiety-like behavior in rats selectively bred for high alcohol drinking.
Alcoholism Clinical and Experimental Research 07/2008; 32(8):1380-7. · 3.34 Impact Factor
