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1.  An fMRI study of behavioral response inhibition in adolescents with and without histories of heavy prenatal alcohol exposure 
Behavioural brain research  2014;278:137-146.
Heavy prenatal alcohol exposure results in a range of deficits, including both volumetric and functional changes in brain regions involved in response inhibition such as the prefrontal cortex and striatum. The current study examined blood oxygen level-dependent (BOLD) response during a stop signal task in adolescents (ages 13–16 y) with histories of heavy prenatal alcohol exposure (AE, n = 21) and controls (CON, n = 21). Task performance was measured using percent correct inhibits during three difficulty conditions: easy, medium, and hard. Group differences in BOLD response relative to baseline motor responding were examined across all inhibition trials and for each difficulty condition separately. The contrast between hard and easy trials was analyzed to determine whether increasing task difficulty affected BOLD response. Groups had similar task performance and demographic characteristics, except for full scale IQ scores (AE < CON). The AE group demonstrated greater BOLD response in frontal, sensorimotor, striatal, and cingulate regions relative to controls, especially as task difficulty increased. When contrasting hard vs. easy inhibition trials, the AE group showed greater medial/superior frontal and cuneus BOLD response than controls. Results were unchanged after demographics and FAS diagnosis were statistically controlled. This was the first fMRI study to utilize a stop signal task, isolating fronto-striatal functioning, to assess response inhibition and the effects task difficulty in adolescents with prenatal alcohol exposure. Results suggest that heavy prenatal alcohol exposure disrupts neural function of this circuitry, resulting in immature cognitive processing and motor-association learning and neural compensation during response inhibition.
PMCID: PMC4382425  PMID: 25281280
fMRI; Fetal alcohol spectrum disorders (FASD); Fetal alcohol syndrome (FAS); Prenatal alcohol exposure; Response inhibition
2.  Effects of Prenatal Alcohol and Cigarette Exposure on Offspring Substance Use in Multiplex, Alcohol-Dependent Families 
Prenatal exposures to alcohol, cigarettes, and other drugs of abuse are associated with numerous adverse consequences for affected offspring, including increased risk for substance use and abuse. However, maternal substance use during pregnancy appears to occur more often in those with a family history of alcohol dependence. Utilizing a sample that is enriched for familial alcohol dependence and includes controls selected for virtual absence of familial alcohol dependence could provide important information on the relative contribution of familial risk and prenatal exposures to offspring substance use.
A sample of multigenerational families specifically ascertained to be at either high or low risk for developing alcohol dependence (AD) provided biological offspring for a longitudinal prospective study. High-Risk families were selected based on the presence of two alcohol dependent sisters. Low-Risk families were selected on the basis of minimal first and second degree relatives with AD. High-Risk (HR=99) and Low-Risk offspring (LR=110) were assessed annually during childhood and biennially in young-adulthood regarding their alcohol, drug, and cigarette use. At the first childhood visit mothers were interviewed concerning their prenatal use of substances.
High-Risk mothers were more likely to use alcohol, cigarettes, and other drugs during pregnancy than Low-Risk control mothers, and to consume these substances in greater quantities. Across the sample, prenatal exposure to alcohol was associated with increased risk for both offspring cigarette use and substance use disorders (SUD), and prenatal cigarette exposure was associated with increased risk for offspring cigarette use. Controlling for risk status by examining patterns within the HR sample, prenatal cigarette exposure remained a specific predictor of offspring cigarette use, and prenatal alcohol exposure was specifically associated with increased risk for offspring SUD.
Women with a family history of SUD are at increased risk for substance use during pregnancy. Both familial loading for alcohol dependence and prenatal exposure to alcohol or cigarettes are important risk factors in the development of offspring substance use. An inadequate assessment of family history may obscure important interactions between familial risk and prenatal exposures on offspring outcomes.
PMCID: PMC4293090  PMID: 25581650
Family history of alcoholism; prenatal alcohol exposure; prenatal cigarette exposure; offspring substance use
3.  Familial risk for alcohol dependence and developmental changes in BMI: the moderating influence of addiction and obesity genes 
Pharmacogenomics  2014;15(10):1311-1321.
Familial loading for alcohol dependence (AD) and variation in genes reported to be associated with AD or BMI were tested in a longitudinal study.
Materials & methods
Growth curve analyses of BMI data collected at approximately yearly intervals and obesity status (BMI > 30) were examined.
High-risk males were found to have higher BMI than low-risk males, beginning at age 15 years (2.0 kg / m2 difference; p = 0.046), persisting through age 19 years (3.3 kg/m2 difference; p = 0.005). CHRM2 genotypic variance predicted longitudinal BMI and obesity status. Interactions with risk status and sex were also observed for DRD2 and FTO gene variation.
Variation at loci implicated in addiction may be influential in determining susceptibility to increased BMI in childhood and adolescence.
PMCID: PMC4161958  PMID: 25155933
addiction; BMI; familial risk for alcoholisml; multiplex families; obesity genes
4.  Effect of Predictive Cuing on Response Inhibition in Children with Heavy Prenatal Alcohol Exposure 
Heavy prenatal exposure to alcohol leads to widespread cognitive deficits, including problems with attention and response inhibition. This study examined blood oxygen level-dependent (BOLD) response in children with and without histories of heavy prenatal alcohol exposure during a task of response inhibition consisting of cued and non-cued trials.
Children and adolescents (ages 8-18y) with (AE=20) and without (CON=15) histories of heavy prenatal exposure to alcohol underwent functional magnetic resonance imaging (fMRI) while performing a go/no-go task. Unbeknownst to subjects, a predictive cue preceded the no-go stimulus in 87% of trials.
Groups were matched on demographic variables and did not differ on most measures of task performance. However, following cued stimuli, the AE group demonstrated a lower hit rate to go stimuli and more conservative response bias than the CON group. Alcohol-exposed participants demonstrated more activation during no-go trials (inhibition) relative to go trials in the left precuneus, cingulate gyrus, anterior cingulate, and right medial frontal gyrus. During cue-dependent response inhibition, the AE group demonstrated less activation in the left pre-central and post-central gyrus compared to the CON group.
Consistent with previous studies of response inhibition, alcohol-exposed children demonstrated greater frontal and parietal activation when attempting to inhibit prepotent responses than controls, despite similar rates of commission errors. This study further demonstrated that alcohol-exposed children had impaired behavioral performance on cued trials and demonstrated less activation in pre-central and post-central gyri relative to controls on these trials. This investigation provides evidence of impaired behavioral and neural processing of sequential information in FASD, which can help improve inhibition in typical populations.
PMCID: PMC3771541  PMID: 23094678
Fetal alcohol spectrum disorders (FASD); fetal alcohol syndrome (FAS); response inhibition; cognitive control; functional neuroimaging
5.  The Effects of Prenatal Alcohol Exposure and Attention-Deficit/Hyperactivity Disorder on Psychopathology and Behavior 
The present study examined prevalence of psychiatric disorders and behavioral problems in children with and without prenatal alcohol exposure (AE) and attention-deficit/hyperactivity disorder (ADHD).
Primary caregivers of 344 children (8–16y, M=12.28) completed the Computerized Diagnostic Interview Schedule for Children-IV (C-DISC-4.0) and the Child Behavior Checklist (CBCL). Subjects comprised 4 groups: AE with ADHD (AE+, n=85) and without ADHD (AE−, n=52), and non-exposed with ADHD (ADHD, n=74) and without ADHD (CON, n=133). The frequency of specific psychiatric disorders, number of psychiatric disorders (comorbidity), and CBCL behavioral scores were examined using chi-square and ANCOVA techniques.
Clinical groups had greater frequency of all psychiatric disorders, except for anxiety, where the AE− and CON groups did not differ. There was a synergistic effect of AE and ADHD on conduct disorder. For Comorbidity, children with ADHD had increased psychiatric disorders regardless of AE, which did not have an independent effect on comorbidity. For CBCL scores, there were significant main effects of AE and ADHD on all scores and significant AE X ADHD interactions for Withdrawn/Depressed, Somatic Complaints, Attention, and all Summary scores. There was a synergistic effect of AE and ADHD on Externalizing, Total Problems, and Attention Problems.
Findings indicate that ADHD diagnosis elevates children’s risk of psychiatric diagnoses, regardless of AE, but suggest a synergistic relation between AE and ADHD on conduct disorder and externalizing behavioral problems in children. Findings affirm a poorer behavioral prognosis for alcohol-exposed children with ADHD and suggest that more than one neurobehavioral profile may exist for individuals with AE.
PMCID: PMC3524354  PMID: 22974279
Psychiatric disorders; psychopathology; fetal alcohol syndrome (FAS); fetal alcohol spectrum disorders (FASD); attention-deficit/hyperactivity disorder (ADHD)
6.  Executive Function Predicts Adaptive Behavior in Children with Histories of Heavy Prenatal Alcohol Exposure and Attention Deficit/Hyperactivity Disorder 
Purpose of Study
Prenatal exposure to alcohol often results in disruption to discrete cognitive and behavioral domains, including executive function (EF) and adaptive functioning. In the current study, the relation between these two domains was examined in children with histories of heavy prenatal alcohol exposure, non-exposed children with a diagnosis of attention-deficit/hyperactivity disorder (ADHD), and typically developing controls.
As part of a multisite study, three groups of children (8-18y, M = 12.10) were tested: children with histories of heavy prenatal alcohol exposure (ALC, N=142), non-exposed children with ADHD (ADHD, N=82), and typically developing controls (CON, N=133) who did not have ADHD or a history of prenatal alcohol exposure. Children completed subtests of the Delis-Kaplan Executive Function System (D-KEFS) and their primary caregivers completed the Vineland Adaptive Behavior Scales-II (VABS). Data were analyzed using regression analyses.
Analyses showed that EF measures were predictive of adaptive abilities and significant interactions between D-KEFS measures and group were present. For the ADHD group, the relation between adaptive abilities and EF was more general, with three of the four EF measures showing a significant relation with adaptive score. In contrast, for the ALC group, this relation was specific to the nonverbal EF measures. In the CON group, performance on EF tasks did not predict adaptive scores over the influence of age.
These results support prior research in ADHD suggesting that EF deficits are predictive of poorer adaptive behavior and extend this finding to include children with heavy prenatal exposure to alcohol. However, the relation between EF and adaptive ability differed by group, suggesting unique patterns of abilities in these children. These results provide enhanced understanding of adaptive deficits in these populations, as well as demonstrate the ecological validity of laboratory measures of executive function.
PMCID: PMC3412910  PMID: 22587709
Fetal alcohol spectrum disorders (FASD); fetal alcohol syndrome (FAS); ADHD; adaptive function; executive functioning; multi-site study; neurobehavioral profile
Heavy prenatal alcohol exposure leads to widespread cognitive deficits, including problems with spatial working memory (SWM). Neuroimaging studies report structural and functional abnormalities in FASD, but interpretations may be complicated by the co-occurrence of a family history of alcoholism. Since, this history is also linked to cognitive deficits and brain abnormalities, it is difficult to determine the extent to which deficits are unique to prenatal alcohol exposure.
Age-matched subjects selected from two neuroimaging studies, underwent functional imaging while engaging in a task assessing memory for spatial locations relative to a vigilance condition assessing attention. Pairwise comparisons were made for the following three groups: children with histories of heavy prenatal alcohol exposure (ALC, n=18); those with no prenatal alcohol exposure, but a confirmed family history of alcoholism (FHP, n=18); and non-exposed, family history negative controls (CON, n=17).
Relative to CON and FHP, the ALC group showed increased BOLD response in the left middle and superior frontal gyri for the spatial working memory condition relative to the vigilance condition (SWM contrast). Additionally, the ALC group showed unique BOLD response increases in the left lingual gyrus and right middle frontal gyrus relative to CON, and left cuneus and precuneus relative to FHP. Both ALC and FHP showed greater activation compared to CON in the lentiform nucleus and insular region.
These results confirm previous studies suggesting SWM deficits in FASD. Differences between the ALC group and the CON and FHP groups suggest the left middle and superior frontal region may be specifically affected in alcohol-exposed children. Conversely, differences from the CON group in the lentiform nucleus and insular region for the ALC and FHP groups may indicate this region is associated with family history of alcoholism rather than specifically with prenatal alcohol exposure.
PMCID: PMC3694801  PMID: 23072431
Fetal Alcohol Spectrum Disorders (FASD); Fetal Alcohol Syndrome (FAS); Functional Magnetic Resonance Imaging; Spatial Working Memory; Family History of Alcoholism
8.  Neuropsychological Profile of Executive Function in Girls with Attention-Deficit/Hyperactivity Disorder 
The majority of research on neurobehavioral functioning among children with Attention-Deficit/Hyperactivity Disorder (ADHD) is based on samples comprised primarily (or exclusively) of boys. Although functional impairment is well established, available research has yet to specify a neuropsychological profile distinct to girls with ADHD. The purpose of this study was to examine performance within four components of executive function (EF) in contemporaneously recruited samples of girls and boys with ADHD. Fifty-six children with ADHD (26 girls) and 90 controls (42 girls), ages 8–13, were administered neuropsychological tests emphasizing response inhibition, response preparation, working memory, and planning/shifting. There were no significant differences in age or SES between boys or girls with ADHD or their sex-matched controls; ADHD subtype distribution did not differ by sex. Compared with controls, children with ADHD showed significant deficits on all four EF components. Girls and boys with ADHD showed similar patterns of deficit on tasks involving response preparation and working memory; however, they manifested different patterns of executive dysfunction on tasks related to response inhibition and planning. Girls with ADHD showed elevated motor overflow, while boys with ADHD showed greater impairment during conscious, effortful response inhibition. Girls, but not boys with ADHD, showed impairment in planning. There were no differences between ADHD subtypes on any EF component. These findings highlight the importance of studying boys and girls separately (as well as together) when considering manifestations of executive dysfunction in ADHD.
PMCID: PMC2957961  PMID: 20639299
Attention; Response control; Working memory; Inhibition; Planning; Childhood; Development

Results 1-8 (8)