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Objective: Impulsivity is an important characteristic of many psychiatric disorders, including substance-related disorders. These disinhibitory disorders have a similar underlying genetic diathesis, with each disorder representing a different expression of the same underlying genetic liability. This study assessed whether there is a relationship between impulsivity and alcohol dependence, and their correlations with P3 (P300) amplitude, a proposed endophenotype of alcoholism. Methods: Healthy control subjects (n 5 58) and subjects with DSM-IV diagnosis of alcohol dependence (n 5 57) were assessed with a visual oddball task. Event-Related Potentials (ERPs) were recorded from 61 scalp electrodes and P3 amplitudes measured. Barratt Impulsiveness Scale (BIS), version 11, was used to evaluate impulsivity. Source localization of P3 was computed using low-resolution brain electromagnetic tomography (LORETA). Results: Alcoholic subjects manifested reductions in target P3 amplitudes (po0.0001). Using LORETA, significantly reduced activation was mapped in the cingulate, medial, and superior frontal regions in alcoholic subjects and highly impulsive subjects. Alcoholic subjects had significantly higher scores on the BIS (po0.0001) than nonalcoholic individuals. There were significant negative correlations between total scores on BIS and P3 amplitude (r 5 0.274, p 5 0.003, on Pz; r 5 0.250, p 5 0.007, on Cz). Conclusions: Our results demonstrate a strong frontal focus of reduced activation during processing of visual targets in alcoholic subjects and individuals with higher impulsivity. The findings suggest that impulsivity may be an important factor that underlies the pathogenesis of alcohol dependence. Studies are underway to examine the relationship between impulsivity and ERPs in offspring of alcoholic subjects, and to identify genes associated with the underlying predisposition involved in disinhibitory disorders.

Background: Electroencephalographic (EEG) measures of hemispheric asymmetry in anterior brain activity have been related to a variety of indices of psychopathology and emotionality. However, little is known about patterns of frontal asymmetry in alcohol-dependent (AD) samples. It is also unclear whether psychiatric comorbidity in AD subjects accounts for additional variance in frontal asymmetry, beyond a diagnosis of AD alone. Methods: We compared 193 AD subjects with 108 control subjects on resting brain activity in anterior and posterior regions, as indexed by asymmetries in a band power in the left and right hemispheres. Within the AD group alone, we examined whether comorbid major depressive disorder (MDD) or antisocial personality disorder (ASPD) had effects on regional asymmetry. Results: Compared with control subjects, AD subjects exhibited lower left, relative to right, cortical activation in anterior regions. Evidence that comorbidity in AD subjects accounted for further variance in EEG asymmetry was mixed; AD subjects with comorbid ASPD were not significantly different from those without ASPD, while AD subjects with a lifetime history of MDD showed less asymmetry in anterior regions than those without MDD. Conclusions: Our findings indicate that AD subjects exhibit a pattern of frontal asymmetry similar to that found in other psychiatric groups. Results examining the effects of comorbidity in AD on EEG asymmetry were inconclusive. The implications of our findings for future work are described.

Background: Alcohol dependence is a clinically and etiologically heterogeneous disorder. Accordingly, a variety of subtypes of alcohol-dependent individuals have been proposed, and multiple operational definitions of alcohol use, abuse, and dependence have been used in linkage analyses directed toward detecting genes involved in alcohol use and problems. Here, we develop quantitative phenotypes that characterize drinking patterns among both alcoholic and nonalcoholic subjects, and use these phenotypes in subsequent linkage analyses. Methods: More than 9000 individuals from alcoholic and control families were administered a semistructured interview and personality questionnaire as part of the initial stage of the Collaborative Study on the Genetics of Alcoholism (COGA). A principal component analysis was conducted on items that captured many of the dimensions of drinking and related behaviors, including aspects of alcohol use, antisocial behavior and affective disturbance when drinking, and personality. Factor scores were computed for all individuals. Nonparametric linkage analyses were conducted on these factor scores, in the initial COGA sample consisting of 987 individuals from 105 extended families, and in a replication sample consisting of 1295 individuals from 157 extended families. Results: Three factors were identified, accounting for 68% of the total variance. The most promising regions of linkage appeared for factor 2, on which higher scores indicate a later age of onset of regular drinking and higher harm avoidance. Chromosome 1 yielded consistent evidence of linkage in both samples, with a maximum lod score of 3.3 when the samples were combined for analysis. Consistent suggestion of linkage also was found to chromosome 15. Conclusions: Developing novel phenotypes that more accurately model the effect of influential genes may help efforts to detect genes involved in complex disorders. Applying principal component analysis in the COGA sample provided support for some regions of linkage previously reported in COGA, and identified other new, promising regions of linkage.

Background: There is controversy in the literature regarding the relationship between event-related-potential (ERP) abnormalities in abstinent alcoholics and stimulus-processing modality (i.e., visual versus auditory). The first purpose of this study was to address questions about whether ERP abnormalities observed in alcoholics are modality specific. The second purpose was to employ current source density (CSD) analyses to investigate topographic differences between alcoholics and controls within each modality. Methods: Data were collected from 30 sober male alcoholics and 39 normal males in a typical auditory oddball task and in a visual oddball paradigm with novel stimuli, with an extensive set of 61 scalp electrodes. Visual and quantitative assessment of CSD maps as well as analyses of variances on both raw and normalized ERP data were performed. Results: Positive findings were limited to the N1 and P3 components. The visual N1 amplitude was significantly smaller in alcoholics than in controls at the parietal region; no significant group differences in N1 were found in the auditory modality. Alcoholics had widespread reductions in P3 amplitudes in both modalities compared with controls, although in the frontal region this effect was partially due to the influence of age. These P3 reductions in alcoholics were statistically more pronounced in the posterior compared with the anterior regions regardless of modality. Topographically, sources in CSD maps were weaker in alcoholics than in controls; in the frontal and central regions, the weakness was more pronounced in the auditory modality but, in parietal and occipital regions, it was more pronounced in the visual modality. Conclusions: The results suggest that, in abstinent alcoholics, abnormalities in auditory ERPs may be localized to more anterior sources, while abnormalities in visual ERPs may be localized to more posterior sources. ERP topographic features are more sensitive than amplitude measurements in assessing alcoholic-related modality effects.

Background: The P300 (P3) component of the event related potential has been established as a sensitive risk marker of vulnerability to alcoholism. Most alcoholism studies have focused on men; recent studies indicate that women are equally vulnerable to developing alcoholism. Methods: Visual P3 recorded from 31 electrode positions was evaluated in 44 alcoholic and 60 control women, 24-50 years of age. P3 amplitudes and latencies of the two groups were statistically compared using Analysis of Variance; source localization of surface amplitude values from each group were plotted using a low-resolution brain electromagnetic tomography. Results: The results indicated that alcoholic women had significantly smaller P3 amplitudes in the frontal and central regions compared with controls. Source localization showed lowered activation in alcoholic women in right dorso-lateral prefrontal cortex and the ventro-medial fronto-central regions. Conclusions: The results suggest that P3 is an equally sensitive endophenotypic marker of vulnerability to alcoholism in women. The findings are discussed in terms of functional and physiologic significance of the P3 amplitude in alcoholic women and its relationship to drinking behaviors.

Background: Evidence from P300 studies in both alcohol-dependent and high-risk (HR) individuals suggests that the reduced P300 amplitudes that often characterize these individuals may reflect a deficit in inhibition (hyperexcitability) in the central nervous system. In this context, the mismatch negativity (MMN) was investigated in the male and female HR offspring of alcohol-dependent fathers and a mixed-sex, low-risk (LR) control group. Methods: As subjects read popular materials, they received a random sequence of 500 binaurally presented tones of 600 Hz and 1600 Hz. The designation of the rare stimulus (n= 60 trials) and frequent stimulus (n= 440 trials) was alternated across subjects. Recordings of MMN were made from 61 electrodes; risk group comparisons were restricted to the five frontal midline electrodes: Fpz, Afz, Fz, Fcz, and Cz. The MMN was obtained by calculating the integral of the area under the curve for both the frequent and rare waveforms over an interval from 100 to 190 msec and then subtracting the former from the latter. Results: The primary observation was that MMN responses in the HR group were significantly larger than those in the LR group. In addition, both LR and HR individuals manifested differential responses to the rare and frequent stimuli, and MMN responses in both groups were largest at Fcz and smallest at Fpz. Discussion: The results indicate that individuals at high risk for alcoholism differ electrophysiologically from LR controls. These differences were manifested as larger magnitudes of the MMN. The findings suggest the possibility that as measured by the MMN, individuals at high risk for alcoholism may be characterized by a deficit in inhibition (excessive neural excitation). The presence of these preexisting central nervous system states may lead to ethanol use for self-medication, which then may facilitate the development of both tolerance to and dependence on ethanol.

Background There is substantial evidence for a significant genetic component to the risk for alcoholism. A previous study reported linkage to chromosomes 1, 2, and 7 in a large data set that consisted of 105 families, each with at least three alcoholic members. Methods: AdditionaLgenotyping in the 105 families has been completed in the chromosomal regions identified in the initial analyses, and a replication sample of 157 alcoholic families ascertained under identical criteria has been genotyped. Two hierarchical definitions of alcoholism were employed in the linkage analyses: (1) Individuals who met both Feighner and DSM-111-R criteria for alcohol dependence represented a broad definition of disease; and (2) individuals who met ICD-10 criteria for alcoholism were considered affected under a more severe definition of disease. Results: Genetic analyses of affected sibling pairs supported linkage to chromosome 1 (LOD = 1.6) in the replication data set as well as in a combined analysis of the two samples (LOD = 2.6). Evidence of linkage to chromosome 7 increased in the combined data (LOD = 2.9). The LOD score on chromosome 2 in the initial data set increased after genotyping of additional markers; however, combined analyses of the two data sets resulted in overall lower LOD scores (LOD = 1.8) on chromosome 2. A new finding of linkage to chromosome 3 was identified in the replication data set (LOD = 3.4). Conclusions: Analyses of a second large sample of alcoholic families provided further evidence of genetic susceptibility loci on chromosomes 1 and 7. Genetic analyses also have identified susceptibility loci on chromosomes 2 and 3 that may act only in one of the two data sets.

Recent data collected at six identical electrophysiological laboratories from the large national multisite Collaborative Study on the Genetics of Alcoholism provide evidence for considering the P3 amplitude of the event-related potential as a phenotypic marker for the risk of alcoholism. The distribution of P3 amplitude to target stimuli at the Pz electrode in individuals 16 years of age and over from 163 randomly ascertained control families (n = 687) was compared with those from 219 densely affected alcoholic families (n = 1276) in which three directly interviewed first-degree relatives met both DSM-III-R and Feighner criteria at the definite level for alcohol dependence (stage II). The control sample did not exclude individuals with psychiatric illness or alcoholism to obtain incidence rates of psychiatric disorders similar to those of the general population. P3 amplitude data from control families was converted to Z-scores, and a P3 amplitude beyond 2 SD's below the mean was considered an "abnormal trait." When age- and sex-matched distributions of P3 amplitude were compared, members of densely affected stage II families were more likely to manifest low P3 amplitudes (2 SD below the mean) than members of control families, comparing affected and unaffected offspring, and all individuals; all comparisons of these distributions between groups were significant (p < 0.00001). P3 amplitude means were also significantly lower in stage II family members, compared with control family members for all comparisons, namely probands, affected and unaffected individuals (p < 0.0001), and offspring (p < 0.01). Furthermore, affected individuals from stage II families, but not control families, had significantly lower P3 amplitudes than unaffected individuals (p < 0.001). Affected males from stage II families had significantly lower P3 amplitudes than affected females (p < 0.001). Recent linkage analyses indicate that visual P3 amplitude provides a biological phenotypic marker that has genetic underpinnings.

A population association between a regulatory variation in the promoter of the serotonin transporter gene (HTT) and severe alcohol dependence was recently reported. We analyzed this potential association in a large number of systematically ascertained families in the United States; these families had at least three first-degree relatives who were alcohol-dependent. Analyses focused on individuals defined as alcohol-dependent by criteria from ICD-10 and on subsets of these individuals reporting withdrawal-related symptoms. Application of the transmission disequilibrium test did not provide support for either linkage or association between this functional polymorphism and alcohol dependence; there was no significant bias in the transmission of either allele to the alcohol-dependent offspring. We also report that African Americans differ from Caucasians in allele frequencies for this polymorphism.

The present investigation examined the effects of placebo (P), low dose (LD), and high dose (HD) ethanol on auditory event-related potential (AEP) recovery functions in a group of males at high risk to develop alcoholism (HR; n = 23, mean = 22.3 years) and a low risk (LR; n = 27, mean = 23.0 years) control group. Condition order was randomized, with one condition (P, LD, or HD) per day and a minimum 1-day interval between conditions. For each subject, both blood alcohol levels (BALs) measured via breathalyzer, and event-related potentials recorded with the entire 10/20 International System, were assessed prior to and at mean intervals of 20, 60, 90, and 130 min after P, LD, or HD administration. A series of binaural auditory stimuli with randomly interposed interstimulus intervals of 0.5, 1.0, and 10.0 sec were used to elicit the N100 and P200 components of the AEP. Between-groups comparisons indicated that ethanol elicited risk group differences in recovery functions not present at baseline. The differences were manifested in the HR group as larger decrements in P200 amplitude during the ascending blood alcohol curve (acute sensitivity) and more rapid returns of both N100 and P200 to baseline levels during the descending blood alcohol curve (acute tolerance). These findings support Newlin and Thomson's (1990) Differentiator Model, suggesting that LR and HR individuals are differentially sensitive to the effects of ethanol.

Scalp recordings of the P300 component of the event-related potential were made from a group of medication-free, chronic male alcoholics and a control group, participating in a visual Go/No Go reaction time paradigm. Subjects were presented with large and small forms of the letters T and V. The large forms (Go stimuli) required a button press with either the left or right hand, whereas the small forms (NO Go stimuli) required response inhibition. Recordings were made from 31 electrodes that, for statistical analyses, were grouped into five regions: frontal, central, parietal, occipital, and temporal. The results indicated that, in each of the five regions, both Go and NO Go response amplitudes were larger in the controls than in the alcoholics. No group differences in latency were observed in any region. Surface energy (Wang et al., Brain Topogr. 6:193-202, 1994) magnitudes paralleled P300 amplitudes and in the controls, compared with the alcoholics, were larger during both Go and No Go trials. Our findings suggest that abstinent, chronic alcoholics differ electro-physiologically from control individuals. These differences are manifested as widespread reductions in P300 amplitudes during the performance of a simple information processing paradigm. The reduced amplitudes may reflect a deficiency in an inhibitory mechanism proposed to underlie P300 generation.

Using data from The Collaborative Study on the Genetics of Alcoholism, we compare direct interview diagnoses of alcohol dependence to those obtained by history from family members. Using a requirement of three or more positive implications by history, the specificity, sensitivity, and positive predictive values are 98%, 39%, and 45%, respectively. A logistic analysis found the gender of the relative and alcoholism in the informant to be significant, but not the gender of the informant. The partial odds ratio of a diagnosis at interview associated with a positive family history diagnosis was 13.6. The relationship between the informant and relative was significant, with negative reports from an offspring or mate more influential than a negative report from a parent or second-degree relative. We derived a recursive equation to combine a variable number of family history reports, wherein the probabilities associated with a single report are computed from the logistic analysis. This permits the use of family history information both as a proxy for an uninterviewed relative, as well as a second source of information to be used in the analysis of genetic family data.

The mechanisms underlying the blunted response to alcohol administration observed in subjects at risk for alcoholism are poorly understood and may involve GABA-benrodiazepine receptors. The purpose of this study was to investigate if subjects at risk for alcoholism had abnormalities in brain GABA-benzodiazepine receptor function. This study measured the effects of 30 pg/kg (iv) of lorarepam, on regional brain glucose metabolism using positron emission tomography and 2-deoxy-2['8~f~uoro-o-g~ucose in subjects with a positive family history for alcoholism (FP) (n = 12) and compared their response with that of subjects with a negative family history for alcoholism (FN) (n = 21). At baseline, FP subjects showed lower cerebellar metabolism than FN. Lorazepam decreased wholebrain glucose metabolism, and FP subjects showed a similar response to FN in cortical and subcortical regions, but FP showed a blunted response in cerebellum. Lorazepam-induced changes in cerebellar metabolism correlated with its motor effects. The decreased cerebellar baseline metabolism in FP as well as the blunted cerebellar response to lorarepam challenge may reflect disrupted activity of benrodiazepine-GABA receptors in cerebellum. These changes could account for the decreased sensitivity to the motor effects of alcohol and benrodiazepines in FP subjects. HE IMPORTANCE of genetics in alcoholism has been T demonstrated in epidemiological studies showing a higher level of concordance for alcoholism in identical twins than in fraternal twins and by studies documenting a 4-fold increased risk for alcoholism in children of alcoholics than in the general population.'-' The influence of genetics in the differential sensitivity to ethanol has also been demonstrated in studies documenting that subjects at risk for alcoholism, that is children of alcoholics who themselves are not alcoholics, show a blunted response to alcohol when compared with subjects with a negative family history for alcoholism (FN).2,6 A blunted response to alcohol in family-positive subjects (FP) has been documented for the

Cloninger has proposed a tridimensional model as the basis for the classification of personality variants and has developed the Tridimensional Personality Questionnaire (TPQ) as an empirical test of this model. In this study, the TPQ was administered to two groups of young men. One group was comprised of nonalcoholic sons of male alcoholics; the other group consisted of nonalcoholic men with no family history of alcoholism. Since the sons of male alcoholics are considered to be at greater risk to develop alcoholism than the sons of nonalcoholics, it was hypothesized that the two groups would demonstrate differences with regard to one or more personality variants as measured by the TPQ. No statistically significant differences in the three TPQ-subscale scores of the two groups were found.

N THE PAST two decades a plethora of scientific I evidence has been accumulated to support the notion that alcoholism is a familial disorder with the presence of genetic factors. It is now well established that sons of alcoholic fathers are approximately four times more likely to develop alcoholism compared to the male offspring of nonalcoholics.’ Indeed, the evidence supporting the contribution of genetic factors in alcoholism is sufficiently compelling to warrant a search for markers of the genetic influence. It should be noted that the antecedent factors or predisposition toward alcoholism might well be assessed with the use of various strategies. It may be possible to study genetic factors by comparing abstinent alcoholics to control subjects or by comparing abstinent alcoholics with a positive family history to abstinent alcoholics with a negative family history of alcoholism. While this particular strategy may yield interesting findings, the interpretation of the data may be confounded by significant differences in drinking history, differential age of onset of alcohol abuse, as well as numerous other clinical variables such as number and severity of withdrawal episodes, alcohol-related medical complications, etc. A strategy typically used in the study of genetically determined disorders is the use of large family pedigrees. This powerful approach enables the investigator to study large families with alcoholism, and compare them to control families where alcoholism is absent. This particular strategy is most compelling if one studies genetically determined diseases such as Huntington’s disease where the phenotypic expression is easily characterized and specific phenotypic markers are readily available. This ap proach is indeed most powerful to examine the pattern of inheritance. However this method is most difficult to implement without the availability of valid and reliable biological or behavioral markers. In the last few years investigators concerned with the potential role of genetic factors in alcoholism have used the high risk paradigm. Comparing the sons of alcoholic fathers and nonalcoholic fathers is a useful approach for examining potential biologid or behavioral factors associated with a predisposition for alcoholism. This particular strategy has been utilized in biological as well as behavioral investigations, and has already yielded promising data fiom various studies. EEG