Robert A. Zucker

Neuropsychological Executive Functioning in Children at Elevated Risk for Alcoholism: Findings in Early Adolescence

One component of individual risk for alcoholism may involve cognitive vulnerabilities prodromal to alcoholism onset. This prospective study of 198 boys followed between 3 and 14 years of age evaluated neurocognitive functioning across three groups who varied in familial risk for future alcoholism. Measures of intelligence, reward-response, and a battery of neuropsychological executive and cognitive inhibitory measures were used. Executive functioning weaknesses were greater in families with alcoholism but no antisocial comorbidity. IQ and reward-response weaknesses were associated with familial antisocial alcoholism. Executive function effects were clearest for response inhibition, response speed, and symbol-digit modalities. Results suggest that executive deficits are not part of the highest risk, antisocial pathway to alcoholism but that some executive function weaknesses may contribute to a secondary risk pathway.

Anticipating problem alcohol use developmentally from childhood into middle adulthood: what have we learned?

This commentary reviews and comments on six major longitudinal studies from the United States, Great Britain and Finland, that test predictive models of drinking and problem drinking behavior across a developmental span of one to two generations. The large Ns, in two instances involving population samples, and the broad and study-overlapping variable domains make this collection of studies unique and of special interest vis-à-vis the issue of cross-study replicability of findings. Significant cross-study commonalities are noted, involving the strong cross-study replicability of an undercontrol/externalizing domain as both a childhood and adolescent predictor of problem drinking outcomes in early to middle adulthood, the relative autostability of heavy and problem use of alcohol over intervals of time as long as a generation, the utility of early drinking behavior as an index for later drinking outcomes, the relative parallelism (with some exceptions) of male and female findings, albeit with greater predictability of male over female drinking outcomes and the relatively tighter relational networks of drinking and other behavioral characteristics for males. This impressive group of quasi-replications also points the field to address several next-step questions, including: (i) the need to parse the undercontrol/externalizing domain to identify those subcomponential process characteristics that are causal to heavy and problem drinking outcomes; (ii) the need to develop models that will handle more effectively the uneven relationships of negative activity to drinking outcomes, in some instances operating protectively, in other instances operating as risk factors; (iii) the need for more carefully articulated, theoretically driven process models that will specify the ordering, developmental saliency and mediational properties of risk and protective factors as they come on line; and (iv) the need for more developmental testing of trait/context interaction models of problem drinking development.

Childhood sleep problems, early onset of substance use and behavioral problems in adolescence

BACKGROUNDnVery few prospective studies examine the relationship between childhood sleep problems and subsequent substance use. In this study, we examined how sleep problems at ages 3-8 predicted onset of alcohol, cigarette, and marijuana use in adolescence. We also investigated the relationships between childhood sleep problems and adolescent internalizing and externalizing problems.nnnMETHODSnStudy participants were 292 boys and 94 girls from a community sample of high risk families and controls in an ongoing longitudinal study.nnnRESULTSnControlling for parental alcoholism, sleep problems at ages 3-8 predicted onset of alcohol, cigarette, and marijuana use among boys and onset of alcohol use among girls. Childhood sleep problems were related to maternal ratings of internalizing and externalizing problems during adolescence for both boys and girls. Adjusting for these problems did not weaken the effects of sleep problems on onset of substance use.nnnCONCLUSIONSnThis is to our knowledge the first study that prospectively examines gender differences in the relationship between sleep problems and early onset of substance use. Childhood sleep problems predicted early onset of substance use for boys but not girls. If childhood sleep problems indeed increase the probability of substance use onset, greater attention by parents to sleep problems in children and adolescents would potentially have ameliorative long-term effects. Parents are encouraged to explore different ways to help their children sleep better, including obtaining information and suggestions from their primary care physicians.

Antisocial alcoholism and serotonin-related polymorphisms: Association tests

Central serotonin dysfunction appears to be related to a subtype of alcoholism with antisocial impulsive features (type II; antisocial alcoholism). The serotonergic deficit may be associated with greater impulsivity, which in turn facilitates both alcohol dependence and antisocial behavior. The present study tested association of antisocial impulsive alcoholism with candidate genes related to serotonergic neurotransmission, using families. Eight markers were assayed using polymerase chain reaction: tryptophan hydroxylase (intron 7), the serotonin transporter SLC6A4 (VNTR 9/12), HTTLPR, the three serotonin receptor types HTR1B (G861C), HTR2A (T102C) and HTR2C (Cys23Ser), monoamine oxidase A (T1460C), and (CA)n. Eligible probands had early age of onset of alcoholism, child conduct disorder, and two or more symptoms of adult Antisocial Personality Disorder. This sample included 35 probands, their parents, and some siblings (n u2009=u2009116). Association tests were conducted using the Haplotype Relative Risk method for antisocial alcoholism diagnosis and the George–Elston regression method (the S.A.G.E. program ASSOC) for quantitative antisocial alcoholism severity. Haplotype Relative Risk analyses were not significant at the 0.05 level for any of the markers. Trends suggestive for future research occurred for tryptophan hydroxylase and HTR2A. Quantitative ASSOC analyses showed significant marker effects (P <0.05) for both monoamine oxidase A markers, which were in linkage disequilibrium. Antisocial alcoholism symptom severity was higher with monoamine oxidase A C homozygotes or hemizygotes, indicating that low monoamine oxidase activity may be important. Future studies are needed to examine joint and interactive effects of serotonin-related markers.

Husbands’ and Wives’ Alcohol Use Disorders and Marital Interactions as Longitudinal Predictors of Marital Adjustment

In this longitudinal study, the relationships among wives and husbands lifetime alcoholism status, marital behaviors, and marital adjustment were tested. Participants were 105 couples from the Michigan Longitudinal Study (MLS), an ongoing multimethod investigation of substance use in a community-based sample of alcoholics, nonalcoholics, and their families. At baseline (T1), husbands and wives completed a series of diagnostic measures, and lifetime diagnosis of alcohol use disorder (AUD, as defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed.), was assessed. Couples completed a problem-solving marital interaction task 3 years later at T2, which was coded for the ratio of positive to negative behaviors. Couples also completed a measure of marital adjustment at T4 (9 years after T1 and 6 years after T2). Results showed that husbands lifetime AUD predicted lower levels of their wifes positive marital behaviors 3 years later but was not related to their own or their wifes marital adjustment 9 years from baseline. By contrast, wives lifetime AUD had direct negative associations with their own and their husbands marital satisfaction 9 years later, and wives marital behaviors during the problem-solving task predicted their own and their husbands marital satisfaction 6 years later. Findings indicate that marital adjustment in alcoholic couples may be driven more by the wives than the husbands AUD and marital behavior. Implications for intervention with alcoholic couples were discussed.

Indirect Effect of Corticotropin-Releasing Hormone Receptor 1 Gene Variation on Negative Emotionality and Alcohol Use via Right Ventrolateral Prefrontal Cortex

Variations in the corticotropin-releasing hormone receptor 1 (CRHR1) gene have been found to interact with stress in modulating excessive alcohol consumption. However, the neural mechanisms through which CRHR1 influences this risk in humans is largely unknown. This study examined the influence of an intronic CRHR1 gene variant, rs110402, on brain responses to negative emotional words, negative emotional traits, and alcohol use in adolescents and young adults at high risk for alcoholism. Childhood stress was investigated as a potential moderator. Using functional magnetic resonance imaging, we found that a region in the right ventrolateral prefrontal cortex (rVLPFC) was more engaged during negative emotional word processing in G homozygotes than in A allele carriers (p(FWE corrected) < 0.01, N = 77). Moreover, an indirect effect of genotype on negative emotionality via rVLPFC activation (p < 0.05, N = 69) was observed, which was further moderated by childhood stress (p < 0.05, N = 63). Specifically, with low childhood stress, G homozygotes exhibited lower levels of negative emotionality associated with greater rVLPFC activation, suggesting that the rVLPFC is involved in reappraisal that neutralizes negative emotional responses. In addition, we found that genotype indirectly modulated excessive alcohol consumption (p < 0.05, N = 69). Specifically, G homozygotes showed greater rVLPFC activation and had lower levels of negative emotionality, which were associated with fewer binge-drinking days and fewer alcohol related problems. This work provides support for a model in which CRHR1 gene variation modulates the risk of problem drinking via an internalizing/negative affect pathway involving rVLPFC and reappraisal of negative emotion.

Impulsiveness mediates the association between GABRA2 SNPs and lifetime alcohol problems

Genetic variants in GABRA2 have previously been shown to be associated with alcohol measures, electroencephalography (EEG) β waves and impulsiveness‐related traits. Impulsiveness is a behavioral risk factor for alcohol and other substance abuse. Here, we tested association between 11 variants in GABRA2 with NEO‐impulsiveness and problem drinking. Our sample of 295 unrelated adult subjects was from a community of families with at least one male with DSM‐IV alcohol use diagnosis, and from a socioeconomically comparable control group. Ten GABRA2 SNPs (single‐nucleotide polymorphisms) were associated with the NEO‐impulsiveness (Pu2009<u20090.03). The alleles associated with higher impulsiveness correspond to the minor alleles identified in previous alcohol dependence studies. All ten SNPs are in linkage disequilibrium (LD) with each other and represent one effect on impulsiveness. Four SNPs and the corresponding haplotype from intron 3 to intron 4 were also associated with Lifetime Alcohol Problems Score (LAPS, Pu2009<u20090.03) (not corrected for multiple testing). Impulsiveness partially mediates (22.6% average) this relation between GABRA2 and LAPS. Our results suggest that GABRA2 variation in the region between introns 3 and 4 is associated with impulsiveness and this effect partially influences the development of alcohol problems, but a direct effect of GABRA2 on problem drinking remains. A potential functional SNP rs279827, located next to a splice site, is located in the most significant region for both impulsiveness and LAPS. The high degree of LD among nine of these SNPs and the conditional analyses we have performed suggest that all variants represent one signal.

Rule breaking mediates the developmental association between GABRA2 and adolescent substance abuse

BACKGROUNDnThis studys primary aim was to examine age-specific associations between GABRA2, rule breaking, problematic alcohol use, and substance abuse symptomatology. The secondary aim was to examine the extent to which rule breaking mediates the GABRA2-substance abuse relationship.nnnMETHODSnA sample (nxa0=xa0518) of primarily male (70.9%) and White (88.8%) adolescents from the Michigan Longitudinal Study was assessed from ages 11-18. Age-specific effects of GABRA2 on rule breaking, problematic alcohol use, and substance abuse symptomatology were examined using nested path models. The role of rule breaking as a mediator in the association between GABRA2 and substance abuse outcomes was tested using prospective cross-lagged path models.nnnRESULTSnGABRA2 is significantly (pxa0<xa00.05) associated with rule breaking in mid- to late-adolescence, but not substance abuse symptomatology across adolescence. GABRA2 effects on problematic alcohol use and substance abuse symptomatology operate largely (45.3% and 71.1%, respectively, pxa0<xa00.05) via rule breaking in midadolescence.nnnCONCLUSIONSnGABRA2 represents an early risk factor for an externalizing pathway to the development of problematic alcohol and drug use.

Brain activation to negative stimuli mediates a relationship between adolescent marijuana use and later emotional functioning

Highlights • Adolescent marijuana use and emotional functioning across time points were examined.• Resiliency increased in controls but not heavy marijuana users across time points.• Negative emotionality decreased in controls but not heavy marijuana users across time points.• Heavy marijuana users had blunted brain activity to negative words relative to controls.• Brain activity mediated the effect of marijuana use on later emotional functioning.

The Prospective Relationship Between Binge Drinking and Physician Visits Among Older Adults

Objectives: The objectives are to (a) determine if binge drinking is related to physician visits and (b) estimate the degree to which the relationship between binge drinking and physician visits can be explained by other health characteristics. Method: Data on a sample of 4,960 older adults (70+ years of age in 2002) from the Health and Retirement Study (HRS) were used. Three linear regression models estimated the impact of binge drinking on physician visits. Results: In the fully adjusted models, binge drinking did have an effect on the number of physician visits by older adults, with more frequent binge drinkers having fewer physician visits. This negative relationship exists even when demographic as well as other current health characteristics are controlled. Discussion: The implications of these results are discussed in terms of more broadly communicating the risks associated with binge drinking and more effectively targeting interventions to older binge drinkers.